Stem Cell Treatment for Erectile Dysfunction

Stem Cell Treatment for Erectile Dysfunction

STEM CELL TREATMENT ERECTILE DYSFUNCTION

Stem Cell Treatment for Erectile Dysfunction

  • Erectile Dysfunction is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance.

  • Stem Cell Treatmentst aims to effect the Calcium-sensitive potassium channel and therefore help increase the flow of blood into the Corpus.

STEM CELL TREATMENT ERECTILE DYSFUNCTIONA penile erection is the hydraulic effect of blood entering and being retained in sponge-like bodies within the penis. The process is often initiated as a result of sexual arousal, when signals are transmitted from the brain to nerves in the penis. Erectile dysfunction is indicated when an erection is difficult to produce. There are various circulatory causes, including alteration of the voltage-gated potassium channel, as in arsenic poisoning from drinking water.

The most important organic causes are cardiovascular disease and diabetes, neurological problems (for example, trauma from prostatectomy surgery), hormonal insufficiencies (hypogonadism) and drug side effects.

Psychological impotence is where erection or penetration fails due to thoughts or feelings (psychological reasons) rather than physical impossibility; this is somewhat less frequent but often can be helped. Notably in psychological impotence, there is a strong response to placebo treatment. Erectile dysfunction, tied closely as it is about ideas of physical well being, can have severe psychological consequences.

Stem Cell Treatment for Erectile Dysfunction

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Related Articles Gene transfer for erectile dysfunction: will this novel therapy be accepted by urologists? Curr Opin Urol. 2009 Nov;19(6):595-600 Authors: Melman A, Rojas L, Christ G Abstract PURPOSE OF REVIEW: The purpose of this review is to update the results of the only phase 1 erectile dysfunction gene transfer trial and based upon those results present the outcome of a web-based survey that studied whether or not knowledgeable in the field urologists would use gene transfer in their patients once approved for use by the US Food and Drug Administration. RECENT FINDINGS: The results of the clinical trials showed no transfer-related serious adverse events. The response to 10 questions of a web-based survey indicates that gene transfer as a first or second-line therapy for practicing urologists would be well accepted. SUMMARY: Practicing, experienced urologists, after the US Food and Drug Administration approval, are willing to employ gene transfer therapies in their patients, be it men who have failed or dissatisfied with other treatments or as shown in up to one-third of men as a first therapy. That outcome portends for rapid adaptation and active participation into the medical practice for maxi-K or other specific gene transfer, stem cell, or combinations that will be developed in the future. PMID: 19741539 [PubMed - indexed for MEDLINE]
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Related Articles Increased levels of osteocalcin-positive endothelial progenitor cells in patients affected by erectile dysfunction and cavernous atherosclerosis. J Sex Med. 2010 Feb;7(2 Pt 1):751-7 Authors: Foresta C, De Toni L, Biagioli A, Ganz F, Magagna S, Caretta N Abstract INTRODUCTION: Erectile dysfunction (ED) was shown to be the expression of a systemic vascular disease that can precede coronary artery disease of some years. Endothelial progenitor cells (EPCs) are a population of circulating cells with endothelial-regenerative potential that may be reduced in ED and coronary patients. Recently, increased levels of osteocalcin (OCN)-positive EPC have been reported in coronary patients. AIM: Investigate the correlation between OCN-positive EPC and cavernous atherosclerotic lesion in ED patients. METHODS: A total of 35 subjects (20 ED patients and 15 controls) were evaluated in our andrological center and enrolled in the study. MAIN OUTCOME MEASURE: All subjects underwent routine clinical examination. Patients were also evaluated with high resolution echo color doppler of penile districts (intima media thickness [IMT] before and after intracavernous alprostadil injection) and circulating levels of progenitor cells (PC), EPC, and OCN-positive fraction of EPC. RESULTS: A progressive reduction of circulating EPC with the severity of cavernous artery atherosclerosis was found. Conversely circulating OCN-positive EPC levels undergo to a significant increase with cavernous atherogenesis progression. CONCLUSIONS: OCN-positive EPC levels in association with penile-color Doppler ultrasound evaluation of cavernous IMT could be predictive markers of subsequent coronary artery disease in ED patients. PMID: 19796016 [PubMed - indexed for MEDLINE]
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Related Articles Purification of human muscle-derived cells using an immunoselective method for potential use in urological regeneration. BJU Int. 2010 Jun;105(11):1598-603 Authors: Lu SH, Yang AH, Chen KK, Chiang HS, Chang LS Abstract OBJECTIVE: To purify human muscle-derived cells (hMDCs) that could be used for managing urinary incontinence, erectile dysfunction and for bladder reconstitution. MATERIALS AND METHODS: hMDCs isolated by a modified preplate technique (MPT) from skeletal muscles of limbs were purified by CD34 antibody and magnetic Dynabeads cell selection system (MDCSS). The growth-doubling time of the hMDCs and purified hMDCs was measured. The purified hMDCs were characterized by flow cytometry, immunofluorescence and confocal laser scanning microscopy. RESULTS: The growth-doubling time of hMDCs was approximately 24 h, which increased to 35 h after purifying using the MDCSS. There were scanty fibroblasts after purification and the MDCSS-purified hMDCs were identified by high expression of stem cell markers and myoblast markers. The expression proportion of the stem cell marker CD34 and myoblast marker CD56 in the hMDCs was higher after purification (MDCSS) than before (MPT), at 32.13% vs 4.12% and 21.56% vs 8.60%, respectively. CONCLUSIONS: The purification of hMDCs showing high expression of stem cell and myoblast markers is feasible. These purified hMDCs could potentially be used for urological regeneration. PMID: 19912190 [PubMed - indexed for MEDLINE]
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Related Articles Superoxide dismutase - a target for gene therapeutic approach to reduce oxidative stress in erectile dysfunction. Methods Mol Biol. 2010;610:213-27 Authors: Deng W, Bivalacqua TJ, Champion HC, Hellstrom WJ, Murthy SN, Kadowitz PJ Abstract Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. Oxidative stress has been demonstrated to be involved in the pathophysiology of age- or diabetes-related ED. Superoxide dismutase (SOD), an antioxidant enzyme catalyzing the conversion of superoxide anion (O(2) (-)) to hydrogen peroxide (H(2)O(2)) and molecular oxygen (O(2)), is a promising therapeutic target for ED. In vivo gene therapy and adult stem cell-based ex vivo gene therapy are two attractive current gene therapies for the treatment of ED. In this chapter we describe the use of two potent gene transfer techniques to deliver the therapeutic gene extracellular superoxide dismutase (ecSOD) into the penis of aged or diabetic rats for therapy of ED: adenoviral-mediated intracavernosal ecSOD gene transfer for gene therapy of ED and ecSOD gene-modified marrow stromal cells, also known as mesenchymal stem cells, based stem cell and gene therapy. PMID: 20013181 [PubMed - indexed for MEDLINE]
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Related Articles POEMS syndrome - a unique presentation of a rare paraneoplastic syndrome. BMJ Case Rep. 2010;2010 Authors: Livingston J, Cobiella C, Hall-Craggs MA Abstract POEMS (peripheral neuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome is a rare multisystem paraneoplastic disorder. A 40-year-old male with a history of peripheral neuropathy and erectile dysfunction presented with a pathological fracture of the neck of the femur, found to be a solitary plasmacytoma. Additional unusual features included splenomegaly, hyperprolactinaemia and skin changes. The patient had a total hip replacement at a specialist orthopaedic hospital and is due to undergo radiotherapy to the femoral lesion and autologous stem cell transplantation. PMID: 22798312 [PubMed - indexed for MEDLINE]
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Related Articles Treatment of erectile dysfunction in the obese type 2 diabetic ZDF rat with adipose tissue-derived stem cells. J Sex Med. 2010 Jan;7(1 Pt 1):89-98 Authors: Garcia MM, Fandel TM, Lin G, Shindel AW, Banie L, Lin CS, Lue TF Abstract INTRODUCTION: Erectile dysfunction (ED) is a major complication of type 2 diabetes, and many diabetic men with ED are refractory to common ED therapies. AIM: To determine whether autologous adipose tissue-derived stem cells (ADSCs) injected into the penis of impotent type 2 diabetic rats improve erectile function. MAIN OUTCOME MEASURES: Blood glucose levels, intracavernous pressure (ICP) increase upon cavernous nerve (CN) electrostimulation, and immunohistochemistry. METHODS: Twenty-two male Zucker diabetic fatty (ZDF) rats were used. At 22 weeks of age, all the animals underwent unilateral CN electrostimulation and ICP measurement to confirm impotence. Paragonadal adipose tissue was harvested to procure ADSCs. The impotent animals were randomized to ADSC treatment and sham control groups. At 23 weeks of age, the treatment group animals underwent a penile injection of 1 million ADSCs; the control group animals received vehicle only. Erectile function studies were repeated at 26 weeks of age, followed by tissue harvest. RESULTS: The rats developed diabetes within the first 10 weeks of age. At 22 weeks of age, 20 out of the 22 rats presented with ED. The post-treatment ICP increase during CN stimulation and ICP increase/mean arterial pressure were significantly higher in the treatment group compared with controls. Three weeks after injection into the corpus cavernosum, only a small number of BrdU-labeled ADSCs was detectable within corporal tissue of the treatment group. There was a significant increase in neuronal nitric oxide synthase (nNOS) in the penile dorsal nerve and in the number of endothelial cells in the corpora cavernosa of the rats in the treatment group. CONCLUSION: Autologous ADSCs injected into the penis were effective to improve erectile function and to alter the microarchitecture of the corpus cavernosum. Since the number of ADSCs retained in the corpus cavernosum is very small, we postulate that their paracrine function, not trans-differentiation to smooth muscle or endothelial cells, is responsible for the improvement in penile function. PMID: 20104670 [PubMed - indexed for MEDLINE]
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Related Articles [Progress in researches on stem cell therapy for erectile dysfunction]. Zhonghua Nan Ke Xue. 2009 Oct;15(10):937-40 Authors: Jiang YB, Gou X Abstract Erectile dysfunction (ED) commonly results from endothelial dysfunction and erectile nerve damage. Recent researches have focused on the preclinical studies of stem cell-based therapies targeted at repairing penile endothelium and protecting erectile nerves. Early studies showed that stem cell- or gene-modified stem cell-based therapies may have enduring efficacy and eventually lead to a cure for ED. Such stem cells as embryonic, mesenchymal, muscle-derived and adipose-derived ones and endothelial progenitor cells all have differentiation potentials and obvious advantages in protecting and repairing both nervi erigentes and corpus cavernosum vascular endothelial cells. Stem cell-based therapies promise to be an effective approach to human erectile dysfunction. PMID: 20112746 [PubMed - indexed for MEDLINE]
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Related Articles The effect of intracavernous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model. J Sex Med. 2010 Apr;7(4 Pt 1):1391-400 Authors: Huang YC, Ning H, Shindel AW, Fandel TM, Lin G, Harraz AM, Lue TF, Lin CS Abstract INTRODUCTION: Hyperlipidemia has been associated with erectile dysfunction (ED) via damage to the cavernous endothelium and nerves. Adipose tissue-derived stem cells (ADSC) have been shown to differentiate into endothelial cells and secrete vasculotrophic and neurotrophic factors. AIM: To assess whether ADSC have therapeutic effects on hyperlipidemia-associated ED. METHODS: Twenty-eight male rats were induced to develop hyperlipidemia with a high-fat diet (hyperlipidemic rats, HR). Ten additional male rats were fed a normal diet to serve as controls (normal rats, NR). Five months later, all rats were subjected to ADSC isolation from paragonadal fat. The cells were cultured for 1 week, labeled with 5-ethynyl-2'-deoxyuridine (EdU), and then injected autologously into the corpus cavernosum of 18 HR. The remaining 10 HR rats were injected with phosphate buffered saline (PBS). At 2 and 14 days post-transplantation, four rats in the HR + ADSC group were sacrificed for tracking of the transplanted cells. At 28 days post-transplantation, all remaining rats were analyzed for serum biochemistry, erectile function, and penile histology. MAIN OUTCOME MEASURES: Erectile function was assessed by intracavernous pressure (ICP) measurement during electrostimulation of the cavernous nerve. Cavernous nerves, endothelium, and smooth muscle were assessed by immunohistochemistry. RESULTS: Serum total cholesterol and low-density lipoprotein levels were significantly higher in HR than in NR. High-density lipoprotein level was significantly lower in HR than in NR. Mean ICP/mean arterial pressure ratio was significantly lower in HR + PBS than in NR + PBS or HR + ADSC. Neuronal nitric oxide synthase (nNOS)-positive nerve fibers and endothelial cells were fewer in HR + PBS than in HR + ADSC. Smooth muscle content was significantly higher in both HR groups than in NR. CONCLUSIONS: Hyperlipidemia is associated with abnormalities in both the nerves and endothelium. Treatment with ADSC ameliorates these adverse effects and holds promise as a potential new therapy for ED. PMID: 20141586 [PubMed - indexed for MEDLINE]
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Related Articles Emerging gene and stem cell therapies for the treatment of erectile dysfunction. Nat Rev Urol. 2010 Mar;7(3):143-52 Authors: Harraz A, Shindel AW, Lue TF Abstract Erectile dysfunction is a prevalent condition that leads to significant morbidity and distress, not just for affected men but also for their partners. Very few currently available treatments ameliorate the underlying causes of the disorder and 'cure' the disease state. Much recent effort has been focused on the development of gene and cell-based approaches to rectify the molecular and tissue defects responsible for ED. Gene therapy has been investigated in animal models as a means to restore normal function to the penis; at this time, however, only one human trial has been published in the peer-reviewed literature. Recent gene therapy studies have focused on the modulation of enzymes associated with the NOS/cGMP pathway, and supplementation of trophic factors, peptides and potassium channels. Stem cell therapy has been a topic of interest in more recent years but there are currently very few published reports in animal models and none in human men. Although stem cell therapy offers the potential for restoration of functional tissues, legitimate concerns remain regarding the long-term fate of stem cells. The long-term safety of both gene and stem cell therapy must be thoroughly investigated before large-scale human studies can be considered. PMID: 20157303 [PubMed - indexed for MEDLINE]
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Related Articles Advances in stem cell therapy for the lower urinary tract. World J Stem Cells. 2010 Feb 26;2(1):1-4 Authors: Lin CS Abstract Lower urinary tract diseases are emotionally and financially burdensome to the individual and society. Current treatments are ineffective or symptomatic. Conversely, stem cells (SCs) are regenerative and may offer long-term solutions. Among the different types of SCs, bone marrow SCs (BMSCs) and skeletal muscle-derived SCs (SkMSCs) have received the most attention in pre-clinical and clinical trial studies concerning the lower urinary tract. In particular, clinical trials with SkMSCs for stress urinary incontinence have demonstrated impressive efficacy. However, both SkMSCs and BMSCs are difficult to obtain in quantity and therefore neither is optimal for the eventual implementation of SC therapy. On the other hand, adipose tissue-derived SCs (ADSCs) can be easily and abundantly obtained from "discarded" adipose tissue. Moreover, in several head-on comparison studies, ADSCs have demonstrated equal or superior therapeutic potential compared to BMSCs. Therefore, across several different medical disciplines, including urology, ADSC research is gaining wide attention. For the regeneration of bladder tissues, possible differentiation of ADSCs into bladder smooth muscle and epithelial cells has been demonstrated. For the treatment of bladder diseases, specifically hyperlipidemia and associated overactive bladder, ADSCs have also demonstrated efficacy. For the treatment of urethral sphincter dysfunction associated with birth trauma and hormonal deficiency, ADSC therapy was also beneficial. Finally, ADSCs were able to restore erectile function in various types of erectile dysfunction (ED), including those associated with diabetes, hyperlipidemia, and nerve injuries. Thus, ADSCs have demonstrated remarkable therapeutic potentials for the lower urinary tract. PMID: 21607109 [PubMed]
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Related Articles Effect of mesenchymal stem cell penile transplantation on erectile signaling of aged rats. Andrologia. 2010 Jun;42(3):187-92 Authors: Abdel Aziz MT, El-Haggar S, Mostafa T, Atta H, Fouad H, Mahfouz S, Rashed L, Sabry D, Senbel A, Ali GA Abstract Stem cell-based therapy targeted at the penile tissue has been lately considered in preclinical studies. This work aimed to assess the effect of intracavernous administration of mesenchymal stem cells (MSCs) in aged rats (n = 100). They were subjected to single intracavernous injection (ICI) of 1.0 million MSCs, followed up for 3, 4 weeks, 3 and 4 months (each group 25 rats) and compared with both adult and aged controls (n = 50). In dissected cavernous tissues, cGMP and histopathology were assessed in addition to intracavernous pressure (ICP) measurement in some anaesthetised rats. The results showed that cavernous tissue cGMP was significantly increased in MSCs transplanted rats in all investigated groups compared with the controls. The mean cavernous cGMP levels after 3 and 4 months of MSCs transplantation were significantly increased compared with those after 3 or 4 weeks. Cavernous tissue ICP measurement showed significant increase in MSCs transplanted groups compared with the controls, more in the long-term follow up than in the shorter one. Histopathological examination detected markedly dilated sinusoidal vascular spaces in the long-term follow-up study. It is concluded that stem cell-based therapy is feasible for age-associated erectile dysfunction and could improve erectile signaling. PMID: 20500748 [PubMed - indexed for MEDLINE]
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Related Articles Injections of adipose tissue-derived stem cells and stem cell lysate improve recovery of erectile function in a rat model of cavernous nerve injury. J Sex Med. 2010 Oct;7(10):3331-40 Authors: Albersen M, Fandel TM, Lin G, Wang G, Banie L, Lin CS, Lue TF Abstract INTRODUCTION: Erectile dysfunction (ED) remains a major complication after radical prostatectomy. The use of adipose tissue-derived stem cells (ADSCs) has shown promising results for the treatment of ED. However, the mechanisms of action for stem cell therapy remain controversial, with increasing evidence pointing to paracrine pathways. AIM: To determine the effects and to identify the mechanism of action of ADSC and ADSC-derived lysate in a rat model of cavernous nerve (CN) crush injury. METHODS: Thirty-two male Sprague-Dawley rats were randomly divided into four equal groups: one group underwent sham operation, while three groups underwent bilateral CN crush. Crush-injury groups were treated at the time of injury with intracavernous injection of ADSC, lysate, or vehicle only (injured controls). Erectile function was assessed by CN electrostimulation at 4 weeks. Penile tissue was collected for histology. MAIN OUTCOME MEASURES:   Intracavernous pressure increase upon CN stimulation; neuronal nitric oxide synthase (nNOS) content in the dorsal penile nerve; smooth muscle content, collagen content, and number of apoptotic cells in the corpus cavernosum. RESULTS: Both ADSC and lysate treatments resulted in significant recovery of erectile function, as compared with vehicle treatment. nNOS content was preserved in both the ADSC and lysate group, with significantly higher expression compared with vehicle-treated animals. There was significantly less fibrosis and a significant preservation of smooth muscle content in the ADSC and lysate groups compared with injured controls. The observed functional improvement after lysate injection supports the hypothesis that ADSCs act through release of intracellular preformed substances or by active secretion of certain biomolecules. The underlying mechanism of recovery appears to involve neuron preservation and cytoprotection by inhibition of apoptosis. CONCLUSIONS: Penile injection of both ADSC and ADSC-derived lysate can improve recovery of erectile function in a rat model of neurogenic ED. PMID: 20561166 [PubMed - indexed for MEDLINE]
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Related Articles Treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: preliminary report of 7 cases. Exp Clin Transplant. 2010 Jun;8(2):150-60 Authors: Bahk JY, Jung JH, Han H, Min SK, Lee YS Abstract OBJECTIVES: Stem cells are characterized by self renewal and multipotent differentiation.We report the effects of intracavernosal transplant of human umbilical cord blood stem cells on diabetic erectile dysfunction. MATERIALS AND METHODS: Seven type 2 diabetics who had failed to achieve an erection for at least 6 months despite medications, and who are currently awaiting penile prostheses, participated. All laboratory results were normal, except for impotence and diabetes mellitus. A total of 1.5 x 10(7) human umbilical cord blood stem cells were infused into the corpus cavernosum. No immunosuppressive measures were taken in any of the patients. International index of erectile function-5, SEP, GAQ, erection diary, blood glucose diary, and medication dosage were followed for 9 months. RESULTS: The mean age was 69.5 years (range, 57-87 years). Morning erections were regained in 3 participants within 1 month, and for all except 1 by the third month, and maintained for more than 6 months. Rigidity increased as the result of stem cell therapy alone, but was insufficient for penetration. With the addition of PDE5 inhibitor before coitus, 2 achieved penetration and experienced orgasm, and maintained for more than 6 months; however, 1 participant could not achieved penetration at ninth month. All but 1 reported increased desire. During follow-up, 2 returned for prosthesis, 4 returned to a nonerectile condition at 9 months, and 1 maintained erection sufficient for coitus with medication until the 11th month. Blood glucose levels decreased by 2 weeks, and medication dosages were reduced in all but 1 subject for 4 to 7 months. Glycosylated hemoglobin levels improved after treatment for up to 3 to 4 months. CONCLUSIONS: Human umbilical cord blood stem cell therapy has positive effects on erectile dysfunction and diabetes mellitus. Stem cells and unknown humoral factors of human umbilical cord blood stem cells mediate mechanism may contribute to these positive effects. PMID: 20565373 [PubMed - indexed for MEDLINE]
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Related Articles [Advance of neurogenic erectile dysfunction therapy by stem cells]. Fa Yi Xue Za Zhi. 2010 Jun;26(3):206-9 Authors: Shen HJ, Zhu GY Abstract Neurogenic erectile dysfunction (NED) commonly results from erectile nerve damage. Recent researches have focused on the preclinical study of stem cell-based therapies targeted at repairing and protecting nervi erigentes. In this paper, researches of NESCs, MDSCs, ASCs and MSCs in NED are reviewed. Early studies have demonstrated that stem cells and gene modified stem cells were effective to the therapy of ED, even likely to cure ED. Stem cells are expected to be applied in the clinical therapy of NED. Stem cells as a new therapy technique will bring up a new challenge in forensic clinical medicine. PMID: 20707282 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of nonhematopoietic adult bone marrow stem/progenitor cells isolated by p75 nerve growth factor receptor into the penis rescues erectile function in a rat model of cavernous nerve injury. J Urol. 2010 Oct;184(4):1560-6 Authors: Kendirci M, Trost L, Bakondi B, Whitney MJ, Hellstrom WJ, Spees JL Abstract PURPOSE: Radical prostatectomy for prostate cancer frequently results in erectile dysfunction and decreased quality of life. We investigated the effects of transplanting nonhematopoietic adult bone marrow stem/progenitor cells (multipotent stromal cells) into the corpus cavernosum in a rat model of bilateral cavernous nerve crush injury. MATERIALS AND METHODS: Multipotent stromal cells were isolated from the bone marrow of transgenic green fluorescent protein rats by plastic adherence (rat multipotent stromal cells) or magnetic activated cell sorting using antibodies against p75 low affinity nerve growth factor receptor (p75 derived multipotent stromal cells). Bilateral cavernous nerve crush injury was induced in adult male Sprague-Dawley rats. Immediately after injury 8 rats each were injected intracavernously with phosphate buffered saline (vehicle control), fibroblasts (cell control), rat multipotent stromal cells (cell treatment) or p75 derived multipotent stromal cells (cell treatment). Another 8 rats underwent sham operation (phosphate buffered saline injection). Four weeks after the procedures we assessed erectile function by measuring the intracavernous-to-mean arterial pressure ratio and total intracavernous pressure during cavernous nerve stimulation. RESULTS: Intracavernous injection of p75 derived multipotent stromal cells after bilateral cavernous nerve crush injury resulted in a significantly higher mean intracavernous-to-mean arterial pressure ratio and total intracavernous pressure compared with all other groups except the sham operated group (p <0.05). Rats injected with typical multipotent stromal cells had partial erectile function rescue compared with animals that received p75 derived multipotent stromal cells. Fibroblast (cell control) and phosphate buffered saline (vehicle control) injection did not improve erectile function. Enzyme-linked immunosorbent assay suggested that basic fibroblast growth factor secreted by p75 derived multipotent stromal cells protected the cavernous nerve after bilateral cavernous nerve crush injury. CONCLUSIONS: Transplantation of adult stem/progenitor cells may provide an effective treatment for erectile dysfunction after radical prostatectomy. PMID: 20728109 [PubMed - indexed for MEDLINE]
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Related Articles [Erectile dysfunction: capabilities of cell therapy]. Urologiia. 2010 Jan-Feb;(1):65-71 Authors: Smirnov VN, Pal'tsev MA, Smirnov VA PMID: 20886734 [PubMed - indexed for MEDLINE]
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Related Articles Circulating endothelial progenitor cells and erectile dysfunction: possibility of nutritional intervention? Panminerva Med. 2010 Jun;52(2 Suppl 1):75-80 Authors: Ichim TE, Zhong Z, Mikirova NA, Jackson JA, Hunninghake R, Mansilla E, Marín G, Núñez L, Patel AN, Angle N, Murphy MP, Dasanu CA, Alexandrescu DT, Bogin V, Riordan NH Abstract To provide an overview of molecular and cellular processes involved in erectile dysfunction (ED) with emphasis on circulating endothelial progenitor cells (EPC) and discuss possible nutraceutical means of intervention. A review of literature on Pubmed related to EPC and ED was conducted. Patients with ED appear to possess a reduced number of circulating EPC, which is associated with poor endothelial function possibly as a result of underlying low-grade inflammation. Several studies support the possibility of improving erectile function by inhibition of inflammation as well as administration of various stem cell types. One particularly interesting approach is nutraceutical supplementation to increase circulating EPC, as demonstrated in the product Stem-Kine. Interventions aimed at increasing circulating EPC may have potential in treatment of vascular ED. PMID: 20657539 [PubMed - indexed for MEDLINE]
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Related Articles Future sexual medicine physiological treatment targets. J Sex Med. 2010 Oct;7(10):3269-304 Authors: Burnett AL, Goldstein I, Andersson KE, Argiolas A, Christ G, Park K, Xin ZC Abstract INTRODUCTION: Sexual function in men and women incorporates physiologic processes and regulation of the central and peripheral nervous systems, the vascular system, and the endocrine system. There is need for state-of-the-art information as there is an evolving research understanding of the underlying molecular biological factors and mechanisms governing sexual physiologic functions. AIM: To develop an evidence-based, state-of-the-art consensus report on the current knowledge of the major cellular and molecular targets of biologic systems responsible for sexual physiologic function. METHODS: State-of-the-art knowledge representing the opinions of seven experts from four countries was developed in a consensus process over a 2-year period. MAIN OUTCOME MEASURES: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: Scientific investigation in this field is needed to increase knowledge and foster development of the future line of treatments for all forms of biological-based sexual dysfunction. This article addresses the current knowledge of the major cellular and molecular targets of biological systems responsible for sexual physiologic function. Future treatment targets include growth factor therapy, gene therapy, stem and cell-based therapies, and regenerative medicine. CONCLUSIONS: Scientific discovery is critically important for developing new and increasingly effective treatments in sexual medicine. Broad physiologic directions should be vigorously explored and considered for future management of sexual disorders. PMID: 21029380 [PubMed - indexed for MEDLINE]
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Related Articles Nerve-sparing radical prostatectomy: current concepts in a robotic era. Panminerva Med. 2010 Sep;52(3):223-30 Authors: Srivastava A, Tan G, Grover S, Tewari AK Abstract Recovery of potency sufficient for penetrative intercourse at a year after surgery varies widely. Much of the progress achieved in the past two decades in improving potency outcomes after radical prostatectomy has resulted from an improved appreciation of the anatomic basis of the nerves responsible for erection. Recent studies suggest alternative and more complex course of nerves than previously described. Better appreciation of the variable and often invisible anatomical course of the cavernosal nerves continues to engender innovations in surgical technique to optimize their preservation. Exciting frontiers of research that include efforts in stem cell neural regeneration, development of specific fluorophores and biomarkers, and performing radical prostatectomy under hypothermic conditions may provide much-needed breakthroughs to improving potency outcomes following radical prostatectomy in this current age of improved life expectancy and heightened patient expectations. PMID: 21045779 [PubMed - indexed for MEDLINE]
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Related Articles The future of erectile dysfunction (ED). Arch Esp Urol. 2010 Oct;63(8):740-7 Authors: Porst H Abstract About 30-40 % of ED patients are non-responders to PDE 5 inhibitor monotherapy. Lifestyle modifications and physical activity with weight loss enhance PDE 5 inhibitor responsiveness. The same applies for combination therapies such PDE 5 inhibitors + L-Arginine 3.000mg, PDE 5 inhibitors + statins and PDE 5 inhibitors + Yohimbine. Combination of daily dosing with Tadalafil 5 mg and on demand application of sildenafil or vardenafil can improve responsiveness and erection hardness (personal experiences). Guanylate cyclase activators or RhoA-kinase inhibitors, either as monotherapy or in combination with PDE 5 inhibitors have shown in preclinical settings the potential to improve erectile function and represent targets for new ED drugs in the future. Immunophilin ligands were able to ameliorate erectile function after cavernous nerve injury due to pelvic surgery. Although having shown convincing efficacy both in animals and humans the centrally acting Melanocortin Receptor (MCR) Agonists were given up for ED treatment because of unfavorable side-effects.Promising targets for ED therapy in the future is gene therapy with several targets as well as stem cell therapy with adipose-derived or muscle-derived stem cells. PMID: 21048284 [PubMed - indexed for MEDLINE]
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Related Articles An update on new oral PDE5 inhibitors for the treatment of erectile dysfunction. Nat Rev Urol. 2010 Nov;7(11):603-9 Authors: Palit V, Eardley I Abstract The management of erectile dysfunction (ED) has been revolutionized by the discovery of phosphodiesterase 5 (PDE5) inhibitors, which have been commercially available for more than a decade and are the first-line therapeutic option for men with ED. Sildenafil, vardenafil and tadalafil were approved by the European Medicine Agency and the US FDA for the treatment of ED on the back of their high efficacy rates and favorable safety profiles. However, despite the fact that more than 50 million patients with ED worldwide have been successfully treated with one of these PDE5 inhibitors, some men--most notably those with severe neurologic damage, diabetes mellitus or severe vascular disease--are resistant to the currently available drugs and require more-invasive treatments, such as intracavernosal injection therapy. Partly as a consequence of this, research into alternative therapeutic approaches continues, including the development of new PDE5 inhibitors, centrally acting pharmaceutical agents, and application of molecular technologies such as gene therapy and stem cell therapy. PMID: 21068761 [PubMed - indexed for MEDLINE]
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Related Articles Intracavernous transplantation of bone marrow-derived mesenchymal stem cells restores erectile function of streptozocin-induced diabetic rats. J Sex Med. 2011 Feb;8(2):427-36 Authors: Qiu X, Lin H, Wang Y, Yu W, Chen Y, Wang R, Dai Y Abstract INTRODUCTION: Erectile dysfunction (ED) is a frequent complication of diabetes mellitus. The efficacy of common ED therapies is low for diabetes-associated ED. AIM: To explore the effects of transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) on improving erectile function of streptozocin (STZ)-induced diabetic rats. METHODS: Male Sprague Dawley rats were injected either with STZ to induce diabetes or with citrate buffer as controls. Rat BM-MSCs were harvested and labeled with CM-DiI (Chloromethylbenzamido derivatives of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate), and then transplanted into corporal cavernosum of STZ-induced diabetic rats. Four weeks after transplantation, all rats were analyzed for erectile function and penile histology. MAIN OUTCOME MEASURES: Erectile function was evaluated by the ratio between intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrostimulation of cavernous nerve. Fate of transplanted BM-MSCs was identified using immunofluorescence staining. Smooth muscle and endothelium in corpora cavernosum were assessed using immunohistochemistry. RESULTS: After BM-MSCs transplantation, the ICP/MAP ratio was increased significantly compared with diabetic controls. Content of smooth muscle and endothelium in corporal cavernosa of BM-MSCs transplanted rats was significantly increased compared to diabetic controls. Immunofluorescence analysis demonstrated that CM-DiI-labeled BM-MSCs could stay in corporal cavernosa for at least 4 weeks and some of them expressed von Willebrand Factor, CD31, calponin, or α-smooth muscle actin, cells markers for endothelial cells or smooth muscle cells, respectively. CONCLUSION: Intracavernous transplantation of BM-MSCs had beneficial effects on erectile function of diabetic rats and increased the content of endothelium and smooth muscle in corporal cavernosum. PMID: 21091881 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of endothelial progenitor cells transfected with VEGF165 to restore erectile function in diabetic rats. Asian J Androl. 2011 Mar;13(2):332-8 Authors: Gou X, He WY, Xiao MZ, Qiu M, Wang M, Deng YZ, Liu CD, Tang ZB, Li J, Chen Y Abstract The present study investigated the effect of transplanting endothelial progenitor cells (EPCs) transfected with the vascular endothelial growth factor gene (VEGF165) into the corpora cavernosa of rats with diabetic erectile dysfunction (ED). A rat model of diabetic ED was constructed via intraperitoneal injection of streptozotocin. After streptozotocin treatment, pre-treated EPCs from each of three groups of rats were transplanted into their corpora cavernosa. Our results, following intracavernosal pressure (ICP) monitoring, showed that ICP increased significantly among rats in the trial group when compared to the results from rats in the blank-plasmid and control groups during basal conditions and electrical stimulation (P<0.01 for both comparisons). Histological examination revealed extensive neovascularisation in the corpora cavernosa of rats in the trial group. Fluorescence microscopy indicated that many of the transplanted EPCs in the trial group survived, differentiated into endothelial cells and integrated into the sites of neovascularisation. Based on the results of this study, we conclude that transplantation of VEGF165-transfected EPCs into the corpora cavernosa of rats with diabetic ED restores erectile function. PMID: 21113173 [PubMed - indexed for MEDLINE]
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Related Articles Re: Transplantation of nonhematopoietic adult bone marrow stem/progenitor cells isolated by p75 nerve growth factor receptor into the penis rescues erectile function in a rat model of cavernous nerve injury. M. Kendirci, L. Trost, B. Bakondi, M. J. Whitney, W. J. G. Hellstrom and J. L. Spees J Urol 2010; 184: 1560-1566. J Urol. 2011 Mar;185(3):1158-9; author reply 1159-61 Authors: Albersen M, Lue TF PMID: 21256512 [PubMed - indexed for MEDLINE]
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Related Articles Original immunophenotype of blood endothelial progenitor cells and microparticles in patients with isolated arterial erectile dysfunction and late onset hypogonadism: effects of androgen replacement therapy. Aging Male. 2011 Sep;14(3):183-9 Authors: La Vignera S, Condorelli R, Vicari E, D'Agata R, Calogero A Abstract OBJECTIVE: Blood endothelial progenitor cells (EPCs) and endothelial microparticles (EMPs) have been proposed as markers of endothelial dysfunction. Aim of this study was to evaluate an original immunophenotype of EPCs and EMPs in patients with isolated arterial erectile dysfunction (ED) and late onset hypogonadism (LOH) before and after androgen replacement therapy. MATERIALS AND METHODS: Fifty patients (50-64 years) with ED and LOH were selected. EPC (CD45(neg)/CD34(pos)/CD144(pos)) and EMP (CD45(neg)/CD34(neg)/CD144(pos)) blood concentrations were evaluated by flow cytometry. Thirty patients received androgen replacement therapy (Tostrex® ProStrakan) for 6 months (group A), other 20 patients not received androgen therapy for the contraindications in their clinical history (group B). RESULTS: After 6 months, group B showed IIEF-5 score, peak systolic velocity and acceleration time significantly worse than group A; in addition EPCs and EMPs were significantly higher in group B compared to group A. CONCLUSIONS: Patients with isolated arterial ED and LOH not treated with androgen therapy showed worst vascular parameters measured by penile Doppler and higher EPCs and EMPs compared to treated hypogonadal patients, hence, LOH appears to be an additional vascular risk factor, and these markers may be considered as predictors of cavernous artery disease. Finally, androgen therapy improves endothelial dysfunction. PMID: 21271942 [PubMed - indexed for MEDLINE]
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Related Articles Aerobic physical activity improves endothelial function in the middle-aged patients with erectile dysfunction. Aging Male. 2011 Dec;14(4):265-72 Authors: La Vignera S, Condorelli R, Vicari E, D'Agata R, Calogero A Abstract OBJECTIVE: Physical activity (PhA) has proven to be a protective factor for normal erectile function. The aim of this study was to evaluate the effects of a standard protocol of aerobic PhA on quality of erectile dysfunction (ED) in patients with arterial ED. MATERIALS AND METHODS: Fifty patients (48-62 years) were selected and underwent to standard protocol of aerobic PhA: 150 min of moderate intensity aerobic activity per week (group A). Twenty patients, matched aged, with vascular ED who did not accept to undergo the standard PhA's protocol, represented the control group. All patients were evaluated, by IIEF-5 questionnaire administration, penile eco color doppler and flow-cytometric analysis for detection of serum concentrations of original immunophenotype endothelial progenitor cells (EPCs) = CD45neg/CD34pos/CD144pos and endothelial microparticles (EMPs) = CD45neg/CD34neg/CD144pos. RESULTS: After 3 months, group A showed IIEF 5 score and peak systolic velocity significantly higher (p < 0.05) compared to controls, and significantly lower values (p < 0.05) of acceleration time, in addition serum concentrations of EPCs and EMPs were significantly lower (p < 0.05) in group A compared to controls. CONCLUSIONS: PhA improves quality of arterial ED, without other pharmacological approach, probably by reduced endothelial apoptosis. This study characterises the study of endothelial dysfunction by new cell circulating markers. PMID: 21303218 [PubMed - indexed for MEDLINE]
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Related Articles Combined strategy of mesenchymal stem cell injection with vascular endothelial growth factor gene therapy for the treatment of diabetes-associated erectile dysfunction. J Androl. 2012 Jan-Feb;33(1):37-44 Authors: Qiu X, Sun C, Yu W, Lin H, Sun Z, Chen Y, Wang R, Dai Y Abstract This study was designed to investigate the effect of vascular endothelial growth factor 164 adenovirus (Ad-VEGF(164))-transfected mesenchymal stem cells (MSC) on improving erectile function in diabetic rats. Forty-five male Sprague-Dawley rats were injected with streptozotocin to develop type 1 diabetes, whereas 10 served as normal controls. Diabetic rats were randomly divided into 3 groups: rats that underwent intracavernous injection with phosphate-buffered saline (DM+PBS), unmodified MSCs (DM+MSC), and Ad-VEGF(164)-transfected MSCs (DM+VMSC). Normal controls received intracavernous injection of PBS. Four weeks after injection, erectile function was measured by cavernous nerve electrostimulation. Penile tissue was harvested for histology and enzyme-linked immunoassay. Prior to injection, high expression of VEGF was confirmed in Ad-VEGF(164)-transfected MSCs by enzyme-linked immunoassay. Four weeks after injection, the erectile function, as well as the content of smooth muscle and endothelium in corpus cavernosum increased significantly in the MSC-injected groups compared with the DM+PBS group. There was a significant improvement of erectile function, the content of smooth muscle and endothelium, and the VEGF concentration in the corpus cavernosum in the DM+VMSC group compared with the DM+MSC group. Our study validates the effect of intracavernous injection of MSCs for diabetes-associated erectile dysfunction in an animal model. The combined strategy of MSC injection with VEGF gene therapy-enhanced therapy of MSCs for the treatment of diabetes-associated erectile dysfunction. PMID: 21311050 [PubMed - indexed for MEDLINE]
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Related Articles Words of Wisdom. Re: treatment of erectile dysfunction in the obese type 2 diabetic ZDF rat with adipose tissue-derived stem cells. Eur Urol. 2011 Jan;59(1):168-9 Authors: Ma L, Hellstrom WJ PMID: 21414869 [PubMed]
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Related Articles Circulating endothelial progenitor cells and endothelial microparticles in patients with arterial erectile dysfunction and metabolic syndrome. J Androl. 2012 Mar-Apr;33(2):202-9 Authors: La Vignera S, Condorelli R, Vicari E, D'Agata R, Calogero AE Abstract Blood endothelial progenitor cells (EPC) and microparticles (EMP) have been proposed as markers of endothelial dysfunction. The aim of this study was to evaluate both EPCs and EMPs in patients with arterial erectile dysfunction (ED) and metabolic syndrome (MetS). To accomplish this, 100 patients (ages 45-60 years) with ED and MetS (Adult Treatment Panel III [ATP III] 1999 criteria) and 17 healthy men (ages 44-57 years) were selected. EPC (CD45(neg)/CD34(pos)/CD144(pos)) and EMP (CD45(neg)/CD144(pos)/Annexin V(pos)) blood concentrations were evaluated by flow cytometry, before and after administration of tadalafil (20 mg) on demand for 3 months. Before treatment, EPCs and EMPs were significantly higher in patients compared with healthy men. EPCs increased significantly after tadalafil administration, whereas EMPs did not differ significantly. EPCs correlated positively or negatively with body mass index and with some cavernous artery indices, both before and after tadalafil administration. EMPs showed only positive correlations with body mass index and some cavernous artery indices, both before and after tadalafil administration. Patients with arterial ED and MetS have higher EPCs and EMPs compared with healthy men; hence, these cells may be regarded as markers of cavernous artery dysfunction. Tadalafil administration increased EPCs but not EMPs, suggesting that this compound may play a role in the endothelial repair response. PMID: 21474787 [PubMed - indexed for MEDLINE]
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Related Articles Cavernous nerve repair with allogenic adipose matrix and autologous adipose-derived stem cells. Urology. 2011 Jun;77(6):1509.e1-8 Authors: Lin G, Albersen M, Harraz AM, Fandel TM, Garcia M, McGrath MH, Konety BR, Lue TF, Lin CS Abstract OBJECTIVES: To investigate whether adipose-derived matrix seeded with adipose-derived stem cells (ADSC) can facilitate the repair of injured cavernous nerves (CNs). METHODS: Human and rat adipose tissues were decellularized and fabricated into various forms, including adipose tissue-derived acellular matrix thread (ADMT). ADMT seeded with ADSC were transplanted into subcutaneous space and examined for signs of inflammation. ADSC-seeded ADMTs were then used to repair CN injury in rats, followed by assessment of histology and erectile function. RESULTS: Adipose tissue can be fabricated into acellular matrices of various shapes and sizes, including threads and sheets. Seeding of ADMT occurred rapidly: within 24 hours, 55% of the surface was covered with ADSC and within 1 week, 90% was covered. Transplantation of the seeded ADMT into the subcutaneous space of an allogenic host showed no signs of inflammatory reaction. At 3 months after grafting into CN injury rats, approximately twice as many cells were found on seeded ADMT as on unseeded ADMT. The seeded ADMT also had various degrees of S100 and neuronal nitric oxide synthase expression, suggesting CN axonal ingrowth. Rats grafted with seeded ADMT overall had the best erectile function recovery when compared with those grafted with unseeded ADMT and those ungrafted. However, as a result of large variations, the differences did not reach statistic significance (P = .07). CONCLUSIONS: Grafting of ADSC-seeded matrix resulted in a substantial recovery of erectile function and improvement of histology. However, further refinement of the matrix architecture is needed to improve the success rate. PMID: 21492917 [PubMed - indexed for MEDLINE]
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Related Articles Editorial comment. Urology. 2011 Jun;77(6):e3; author reply e4 Authors: Frauscher F, Marksteiner R PMID: 21624585 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell therapy for erectile dysfunction: a critical review. Stem Cells Dev. 2012 Feb 10;21(3):343-51 Authors: Lin CS, Xin ZC, Wang Z, Deng C, Huang YC, Lin G, Lue TF Abstract Erectile dysfunction (ED) is a prevailing health problem that seriously impacts quality of life. Current treatment options are less effective for patients having cavernous nerve (CN) injury or diabetes mellitus-related ED. These 2 types of ED are thus the main focus of past and current stem cell (SC) therapy studies. In a total of 16 studies so far, rats were exclusively used as disease models and SCs were mostly derived from bone marrow, adipose tissue, or skeletal muscle. For tracking, SCs were labeled with LacZ, green fluorescent protein, 4',6-diamidino-2-phenylindole, DiI, bromodeoxyuridine, or 5-ethynyl-2-deoxyuridine, some of which might have led to data misinterpretation. SC transplantation was done exclusively by intracavernous (IC) injection, which has been recently shown to have systemic effects. Functional assessment was done exclusively by measuring increases of IC pressure during electrostimulation of CN. Histological assessment usually focused on endothelial, smooth muscle, and CN contents in the penis. In general, favorable outcomes have been obtained in all trials so far, although whether SCs had differentiated into specific cell lineages remains controversial. Recent studies have shown that intracavernously injected SCs rapidly escaped the penis and homed into bone marrow. This could perhaps explain why intracavernously injected SCs had systemic antidiabetic effects and prolonged anti-ED effects. These hypotheses and the differentiation-versus-paracrine debate require further investigation. PMID: 21793654 [PubMed - indexed for MEDLINE]
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Related Articles Tracking intracavernously injected adipose-derived stem cells to bone marrow. Int J Impot Res. 2011 Nov-Dec;23(6):268-75 Authors: Lin G, Qiu X, Fandel T, Banie L, Wang G, Lue TF, Lin CS Abstract The intracavernous (i.c.) injection of stem cells (SCs) has been shown to improve erectile function in various erectile dysfunction (ED) animal models. However, the tissue distribution of the injected cells remains unknown. In this study we tracked i.c.-injected adipose-derived stem cells (ADSCs) in various tissues. Rat paratesticular fat was processed for ADSC isolation and culture. The animals were then subject to cavernous nerve (CN) crush injury or sham operation, followed by i.c. injection of 1 million autologous or allogeneic ADSCs that were labeled with 5-ethynyl-2-deoxyuridine (EdU). Another group of rats received i.c. injection of EdU-labeled allogeneic penile smooth muscle cells (PSMCs). At 2 and 7 days post injection, penises and femoral bone marrow were processed for histological analyses. Whole femoral bone marrows were also analyzed for EdU-positive cells by flow cytometry. The results show that ADSCs exited the penis within days of i.c. injection and migrated preferentially to bone marrow. Allogenicity did not affect the bone marrow appearance of ADSCs at either 2 or 7 days, whereas CN injury reduced the number of ADSCs in bone marrow significantly at 7 but not 2 days. The significance of these results in relation to SC therapy for ED is discussed. PMID: 21796145 [PubMed - indexed for MEDLINE]
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Related Articles New immunophenotype of circulating endothelial progenitor cells and endothelial microparticles in patients with erectile dysfunction and metabolic syndrome: effects of tadalafil administration. Int Angiol. 2011 Oct;30(5):415-23 Authors: La Vignera S Abstract AIM: Circulating endothelial progenitor cells (EPCs) and endothelial microparticles (EMPs) increase, respectively, in the attempt to repair the damaged endothelium and in response to endothelial dysfunction. Erectile dysfunction (ED) of arterial origin recognizes endothelial dysfunction as one of its main determinants and shares risk factors and physiopathological evolution with the metabolic syndrome (MetS). Tadalafil, selective inhibitor of phosphodiesterase V, long half-life, is used to treat erectile dysfunction, and several studies have already documented the beneficial effects on endothelial dysfunction. The aim of this paper was to evaluate the concentrations of EPCs and EMPs in patients with arterial ED and MetS, before and after tadalafil administration, and in healthy men. METHODS: Thirty patients (47-54 years) with ED and MetS (ATP III 1999 criteria) and 17 healthy men (44-57 years) were selected. EPCs (CD45neg/CD34pos/CD144pos) and EMPs (CD45neg/CD34neg/CD144pos) blood concentrations were evaluated by flow cytometry before and after administration of tadalafil (20 mg) on demand for 3 months. After treatment, the patients were divided into responders and poor responders, according to their IIEF-5 score. MAIN OUTCOME MEASURES: Blood EPCs and EMPs. RESULTS: Before treatment, the percentage of EPCs and EMPs was significantly higher in patients with ED and MetS compared to healthy men. Treatment with tadalafil increased significantly EPCs in both responders and poor responders. The latter had significantly higher EPCs compared to responders, both before and after tadalafil. Before tadalafil, EMPs were higher, but not significantly, in poor responders vs. responders. No significant change occurred after tadalafil administration in both responders and poor responders. A significant positive correlation was found between EPCs and age, Body Mass Index (BMI), acceleration time, IMT and EDV; whereas a negative correlation was found with IIEF-5 score, PSV and resistance index. EMPs correlated positively with BMI, acceleration time and IMT and negatively with the IIEF-5 score. CONCLUSION: Tadalafil increased the percentage of EPCs in both responders and poor responders, suggesting the persistence of an adequate bone marrow response. The unchanged EMP concentrations after tadalafil suggest a reduction of the dysfunctional mechanism. PMID: 21804479 [PubMed - indexed for MEDLINE]
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Related Articles Recruitment of intracavernously injected adipose-derived stem cells to the major pelvic ganglion improves erectile function in a rat model of cavernous nerve injury. Eur Urol. 2012 Jan;61(1):201-10 Authors: Fandel TM, Albersen M, Lin G, Qiu X, Ning H, Banie L, Lue TF, Lin CS Abstract BACKGROUND: Intracavernous (IC) injection of stem cells has been shown to ameliorate cavernous-nerve (CN) injury-induced erectile dysfunction (ED). However, the mechanisms of action of adipose-derived stem cells (ADSC) remain unclear. OBJECTIVES: To investigate the mechanism of action and fate of IC injected ADSC in a rat model of CN crush injury. DESIGN, SETTING, AND PARTICIPANTS: Sprague-Dawley rats (n=110) were randomly divided into five groups. Thirty-five rats underwent sham surgery and IC injection of ADSC (n=25) or vehicle (n=10). Another 75 rats underwent bilateral CN crush injury and were treated with vehicle or ADSC injected either IC or in the dorsal penile perineural space. At 1, 3, 7 (n=5), and 28 d (n=10) postsurgery, penile tissues and major pelvic ganglia (MPG) were harvested for histology. ADSC were labeled with 5-ethynyl-2-deoxyuridine (EdU) before treatment. Rats in the 28-d groups were examined for erectile function prior to tissue harvest. MEASUREMENTS: IC pressure recording on CN electrostimulation, immunohistochemistry of the penis and the MPG, and number of EdU-positive (EdU+) cells in the injection site and the MPG. RESULTS AND LIMITATIONS: IC, but not perineural, injection of ADSC resulted in significantly improved erectile function. Significantly more EdU+ ADSC appeared in the MPG of animals with CN injury and IC injection of ADSC compared with those injected perineurally and those in the sham group. One day after crush injury, stromal cell-derived factor-1 (SDF-1) was upregulated in the MPG, providing an incentive for ADSC recruitment toward the MPG. Neuroregeneration was observed in the group that underwent IC injection of ADSC, and IC ADSC treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum. CONCLUSIONS: CN injury upregulates SDF-1 expression in the MPG and thereby attracts intracavernously injected ADSC. At the MPG, ADSC exert neuroregenerative effects on the cell bodies of injured nerves, resulting in enhanced erectile response. PMID: 21824718 [PubMed - indexed for MEDLINE]
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Related Articles Arterial erectile dysfunction: reliability of penile Doppler evaluation integrated with serum concentrations of late endothelial progenitor cells and endothelial microparticles. J Androl. 2012 May-Jun;33(3):412-9 Authors: La Vignera S, Vicari E, Condorelli RA, Di Pino L, Calogero AE Abstract We recently showed the diagnostic value of a new immunophenotype of blood endothelial progenitor cells (EPC) (CD45(-)/CD34(+)/CD144(+)) and endothelial microparticles (EMP) (CD45(-)/CD144(+)/annexin V(+)) in patients with arterial erectile dysfunction (AED), particularly in patients with associated late-onset hypogonadism and/or metabolic syndrome. In addition, we evaluated the effects of androgen replacement therapy, aerobic physical activity, and tadalafil administration on these markers. The aim of this study was to evaluate the serum concentrations of EPCs and EMPs in a large cohort of patients with AED according to severity of cavernous arterial insufficiency evaluated by penile Doppler. A total of 120 patients (aged 58.0 ± 6.0 years) with AED were enrolled in this study. Patients were classified into 3 groups based on value of peak systolic velocity (PSV). Group A: 37 patients with PSV <25 cm/s (severe arterial insufficiency); group B: 40 patients with PSV between 25 and 29 cm/s (moderate arterial insufficiency); group C: 43 patients with PSV between 30 and 34 cm/s (mild arterial insufficiency). Twenty patients (aged 60.0 ± 3.0 years) with psychogenic erectile dysfunction (PED) represented the control group. EPC and EMP blood concentrations were evaluated by flow cytometry. Patients with AED had significantly higher blood pressure, triglyceride levels, homeostasis model assessment index of insulin resistance, cavernous artery acceleration time, and intima-media thickness than those with PED, whereas International Index of Erectile Function score, high-density lipoprotein cholesterol level, and cavernous artery PSV were lower than those in PED. Both EPC and EMP levels were significantly higher in patients with AED compared with patients with PED. Among 3 groups of patients with AED, there were no significant differences in metabolic parameters examined, but group A showed significantly higher values of cavernous artery acceleration time and intima-media thickness than group B and group C. Finally, group A showed serum concentrations of EPCs and EMPs significantly higher compared with other groups with AED. Patients with AED showed worse metabolic parameters, cavernous artery parameters, and EPC and EMP levels compared with patients with PED. Among patients with AED, those with PSV <25 cm/s showed worse findings of endothelial dysfunction. This suggests that AED is an expression of endothelial damage and that this original immunophenotype of EPCs and EMPs may be considered a predictor of endothelial dysfunction in patients with AED. Finally, this study confirmed the reliability of penile Doppler evaluation integrated with these serum markers of endothelial dysfunction. PMID: 21868743 [PubMed - indexed for MEDLINE]
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Related Articles [Correlation between hypertension and erectile dysfunction]. Zhonghua Nan Ke Xue. 2011 Aug;17(8):675-81 Authors: Liu JH, Ling Q Abstract The relationship between erectile dysfunction (ED) and hypertension is a focus in andrological research. ED and hypertension share some pathophysiologic pathways, such as oxidative stress-induced endothelial dysfunction and up-regulated RhoA/Rho kinase activity, and both are the diseases at different stages of the pathological process of vascular dysfunction. Thus, it is particularly important to conduct regular and meticulous evaluation of such patients, so as to give rational individualized medication. Phosphodiesterase-5 inhibitors have an excellent efficacy and safety profile in the management of hypertension, either used alone or with antihypertensive medication. At present, gene therapy and adipose-derived stem cell therapy have displayed favorable prospects in the management of ED and hypertension, and translational medicine may help bring more clinical benefits. PMID: 21898987 [PubMed - indexed for MEDLINE]
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Related Articles Adrenomedullin mediates adipose tissue-derived stem cell-induced restoration of erectile function in diabetic rats. J Sex Med. 2012 Feb;9(2):482-93 Authors: Nishimatsu H, Suzuki E, Kumano S, Nomiya A, Liu M, Kume H, Homma Y Abstract INTRODUCTION: Erectile dysfunction (ED) is a major health problem. It is known that diabetic patients are more refractory to common treatments for ED. AIM: To explore the better treatment for ED, we examined the effects of adipose-derived stem cells (ASC) on ED using a diabetic rat model. We also analyzed the cytokines produced by ASC and implicated in ASC-induced restoration of erectile function. METHODS: Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. ASC or adenoviruses were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology and protein expression were analyzed 4 weeks after the injection of ASC or adenoviruses. MAIN OUTCOME MEASURES: Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of proteins specific for vascular endothelial cells (VEC) was assessed by Western blot analysis. RESULTS: ASC restored erectile function especially when they were cultured in medium containing growth factors for VEC. This restoration was associated with improvement in the histology of the cavernous body, and increased expression of VEC markers such as VE-cadherin and endothelial nitric oxide synthase (eNOS). When the expression of adrenomedullin (AM), a vasoactive peptide originally isolated from human pheochromocytoma tissue, was knocked down, the effect of ASC on ED was significantly diminished. Knockdown of AM was associated with decreased expressions of VE-cadherin and eNOS. Furthermore, overexpression of AM induced by adenovirus infection significantly improved erectile function in these diabetic rats. Overexpression of AM was associated with increased expressions of VE-cadherin and eNOS. CONCLUSIONS: These results suggested that ASC have the potentials to restore erectile function and that AM produced by ASC plays a major role in the restoration of erectile function. PMID: 21951711 [PubMed - indexed for MEDLINE]
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Related Articles Stem cells: novel players in the treatment of erectile dysfunction. Asian J Androl. 2012 Jan;14(1):145-55 Authors: Zhang H, Albersen M, Jin X, Lin G Abstract Stem cells are defined by their capacity for both self-renewal and directed differentiation; thus, they represent great promise for regenerative medicine. Historically, stem cells have been categorized as either embryonic stem cells (ESCs) or adult stem cells (ASCs). It was previously believed that only ESCs hold the ability to differentiate into any cell type, whereas ASCs have the capacity to give rise only to cells of a given germ layer. More recently, however, numerous studies demonstrated the ability of ASCs to differentiate into cell types beyond their tissue origin. The aim of this review was to summarize contemporary evidence regarding stem cell availability, differentiation, and more specifically, the potential of these cells in the diagnosis and treatment of erectile dysfunction (ED) in both animal models and human research. We performed a search on PubMed for articles related to definition, localisation and circulation of stem cells as well as the application of stem cells in both diagnosis and treatment of ED. Strong evidence supports the concept that stem cell therapy is potentially the next therapeutic approach for ED. To date, a large spectrum of stem cells, including bone marrow mesenchymal stem cells, adipose tissue-derived stem cells and muscle-derived stem cells, have been investigated for neural, vascular, endothelial or smooth muscle regeneration in animal models for ED. In addition, several subtypes of ASCs are localized in the penis, and circulating endogenous stem cells can be employed to predict the outcome of ED and ED-related cardiovascular diseases. PMID: 22002437 [PubMed - indexed for MEDLINE]
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Related Articles Over-expression of VEGF165 in the adipose tissue-derived stem cells via the lentiviral vector. Chin Med J (Engl). 2011 Oct;124(19):3093-7 Authors: Sun XZ, Liu GH, Wang ZQ, Zheng FF, Bian J, Huang YP, Gao Y, Zhang YD, Deng CH Abstract BACKGROUND: Many researchers studied the possibility of using stem cells as gene therapeutic vector. But few related reports on the adipose tissue-derived stem cells (ADSCs) are available. Therefore we intended to construct a lentiviral VEGF(165) expression vector and then infect the ADSCs to produce therapeutic seed cells. METHODS: EHS1001-68950485313912 clone was mutated by PCR method to produce consensus fragment of VEGF(165) transcript (NM_001025368). Lentivirus was enveloped with pGC-FU, pHelper 1.0 and pHelper 2.0 plasmids in 293T cells. And then the ADSCs (multiplicity of infection = 20) were transfected with the vectors after titer determination. Stable expression of VEGF(165) in ADSCs was confirmed by immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA) and Western blotting analysis. RESULTS: DNA sequencing and 293T transfection verified VEGF(165) was linked to the GFP fused vector. The virus titer is up to 2 × 10(8) determined by quantitative PCR. VEGF(165) transduced cells could show green fluorescence confirmed by immunofluorescence staining (almost 95%). ELISA analyses could detect out the density of VEGF was 850.86 - 1202.13 pg/ml (mean (923.00 ± 31.22) pg/ml) in the supernatant of VEGF(165)-transduced cells but not detected in the GFP-transduced cells (P < 0.001) and the Western blotting analyses also confirmed VEGF(165) expression in VEGF(165)-transduced cells. CONCLUSIONS: The VEGF(165) over-expression ADSCs were obtained and may be used as a cell therapeutic tool and may be applied for vascular regeneration, especially in the treatment of erectile dysfunction. PMID: 22040562 [PubMed - indexed for MEDLINE]
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Related Articles Multipotent stromal cell therapy for cavernous nerve injury-induced erectile dysfunction. J Sex Med. 2012 Feb;9(2):385-403 Authors: Albersen M, Kendirci M, Van der Aa F, Hellstrom WJ, Lue TF, Spees JL Abstract INTRODUCTION: Erectile dysfunction (ED) following radical prostatectomy (RP) is a result of inadvertent damage to the cavernous nerves that run close to the prostate capsula. The mechanisms behind the development of post-RP ED are increasingly recognized and include cavernosal fibrosis and cavernosal smooth muscle apoptosis, resulting from cavernous nerve degeneration due to neuropraxia. In recent years, cell-based therapies have received increasing attention regarding their potential for recovery of erectile function following cavernous nerve injury (CNI). Multipotent stromal cells (MSCs) are an attractive cell source for this application based on their regenerative potential and their clinical applicability. AIM: To review available evidence on the efficacy and mechanisms of action of MSC application for the treatment of ED, with an emphasis on ED following CNI. METHODS: A nonsystematic review was conducted on the available English literature between 1966 and 2011 on the search engines SciVerse-sciencedirect, SciVerse-scopus, Google Scholar, and PubMed. RESULTS: MSCs from both bone marrow and adipose tissue have shown beneficial effects in a variety of animal models for ED. While MSC application in chronic disease models such as diabetes, aging, and hyperlipidemia may result in cell engraftment and possibly MSC differentiation, this observation has not been made in the acute CNI rat model. In the latter setting, MSC effects seem to be established by cell recruitment toward the major pelvic ganglion and local paracrine interaction with the host neural tissue. CONCLUSIONS: While the type of model may influence the mechanisms of action of this MSC-based therapy, MSCs generally display efficacy in various animal models for ED. Before translation to the clinic is established, various hurdles need to be overcome. PMID: 22145667 [PubMed - indexed for MEDLINE]
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Related Articles Comparison of human muscle-derived stem cells and human adipose-derived stem cells in neurogenic trans-differentiation. Korean J Urol. 2011 Dec;52(12):852-7 Authors: Kwon EB, Lee JY, Piao S, Kim IG, Ra JC, Lee JY Abstract PURPOSE: Erectile dysfunction (ED) remains a major complication from cavernous nerve injury during radical prostatectomy. Recently, stem cell treatment for ED has been widely reported. This study was conducted to investigate the availability, differentiation into functional cells, and potential of human muscle-derived stem cells (hMDSCs) and human adipose-derived stem cells (hADSCs) for ED treatment. MATERIALS AND METHODS: We compared the neural differentiation of hMDSCs and hADSCs. Human muscle and adipose tissues were digested with collagenase, followed by filtering and centrifugation. For neural induction, isolated hMDSCs and hADSCs were incubated in neurobasal media containing forskolin, laminin, basic-fibroblast growth factor, and epidermal growth factor for 5 days. Following neural induction, hMDSCs and hADSCs were differentiated into neural cells, including neurons and glia, in vitro. RESULTS: In neural differentiated hMDSCs (d-hMDSCs) and differentiated hADSCs (d-hADSCs), neural stem cell marker (nestin) showed a significant decrease by immunocytochemistry, and neuronal marker (β-tubulin III) and glial marker (GFAP) showed a significant increase, compared with primary hMDSCs and hADSCs. Real-time chain reaction analysis and Western blotting demonstrated significantly elevated levels of mRNA and protein of β-tubulin III and GFAP in d-hADSCs compared with d-hMDSCs. CONCLUSIONS: We demonstrated that hMDSCs and hADSCs can be induced to undergo phenotypic and molecular changes consistent with neurons. The neural differentiation capacity of hADSCs was better than that of hMDSCs. PMID: 22216399 [PubMed]
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Related Articles Whole genome microarray of the major pelvic ganglion after cavernous nerve injury: new insights into molecular profile changes after nerve injury. BJU Int. 2012 May;109(10):1552-64 Authors: Calenda G, Strong TD, Pavlovich CP, Schaeffer EM, Burnett AL, Yu W, Davies KP, Bivalacqua TJ Abstract UNLABELLED: What's known on the subject? and What does the study add? With the present study, we aimed to provide a global picture of the molecular processes that are activated by CN injury. The present study used genomic expression profiling to identify candidate genes that might be useful targets in the CN recovery process and, thus, the ultimate preservation of penile erection. Regeneration of the CN and axonal outgrowth clearly involve changes in multiple biochemical pathways that have never been investigated by microarray analysis. We analyzed global gene expression in the major pelvic ganglion at early stages (48 h and 14 days) after CN injury and focused on the detection of changes in genes related to nervous tissue repair and proliferation. The findings of the present study provide important insight into the molecular systems affected by CN injury and identify candidate genes that may be utilized for novel molecular-based therapies for the preservation and protection of the CN during RP. OBJECTIVES: To to examine the complexity of the many molecular systems involved in supporting cavernous nerve (CN) repair and regeneration in a rat model of bilateral crush injury utilizing a microarray analysis approach. Erectile dysfunction (ED) is a common clinical complication after prostate cancer treatment by radical prostatectomy, and recovery of erectile function can take as long as 2 years. There are gaps in our understanding of the autonomic pelvic innervation of the penis that still need to be addressed for the development of an adequate treatment strategy for post-prostatectomy ED. The molecular mechanisms of the intrinsic ability of CN to regenerate after an injury have not been elucidated. MATERIALS AND METHODS: We analyzed global gene expression in the major pelvic ganglion 48 h and 14 days after CN injury. Overall, a comparative analysis showed that 325 genes changed at the 48-h time point and 114 genes changed at 14 days. There were 60 changed genes in common with both time points. Using the Ingenuity Pathway Analysis® system (Ingenuity Systems, Inc., Redwood City, CA, USA), we were able to analyze the significantly changed genes that were unique and common to each time point by biological function. We focused on the detection of changes related to nervous tissue repair and proliferation, molecular networks of neurotrophic factors, stem cell regulation and synaptic transmission. RESULTS: There was strong evidence of the early mobilization of genes involved in repair and neuroprotection mechanisms (SERPINF1, IGF1, PLAU/PLAUR, ARG1). Genes related to nervous system development (ATF3 GJA1, PLAU, SERPINE1), nerve regeneration (SERPINE2, IGF1, ATF3, ARG1) and synaptic transmission (GJC1, GAL) were changed. Several genes related to proliferation as well as apoptosis (A2M, ATF3, C3, EGR4, FN1, GJA1, GAL) were also changed, possibly as part of a protective mechanism or the initiation of remodelling. CONCLUSIONS: The results obtained show that multiple biological processes are associated with injury and repair of the CN and provide a systematic genome-wide screen for neurotrophic and/or inhibitory pathways of nerve regeneration. These data identify the candidate genes that may be utilized in novel molecular-based therapies for the preservation and protection of the CN during radical prostatectomy. PMID: 22300381 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell-based therapy for erectile dysfunction. Chin Med J (Engl). 2011 Nov;124(22):3810-5 Authors: Wu JH, Xia SJ Abstract OBJECTIVE: To review the effect of stem cells in erectile dysfunction as well as their application to the therapy of erectile dysfunction. DATA SOURCES: The data used in the present article were mainly from PubMed with relevant English articles published from 1974 to 2011. The search terms were "stem cells" and "erectile dysfunction". STUDY SELECTION: Articles regarding the role of stem cells in erectile dysfunction and their application to the therapy of erectile dysfunction were selected. RESULTS: Stem cells hold great promise for regenerative medicine because of their ability to self-renew and to differentiate into various cell types. Meanwhile, in preclinical experiments, therapeutic gene-modified stem cells have been approved to offer a novel strategy for cell therapy and gene therapy of erectile dysfunction. CONCLUSION: The transplantation of stem cells has the potential to provide cell types capable of restoring normal function after injury or degradation in erectile dysfunction. However, a series of problems, such as the safety of stem cells transplantation, their application in cell therapy and gene therapy of erectile dysfunction need further investigation. PMID: 22340246 [PubMed - indexed for MEDLINE]
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Related Articles Mobilisation of endothelial progenitor cells: one of the possible mechanisms involved in the chronic administration of melatonin preventing erectile dysfunction in diabetic rats. Asian J Androl. 2012 May;14(3):481-6 Authors: Qiu XF, Li XX, Chen Y, Lin HC, Yu W, Wang R, Dai YT Abstract Diabetes-induced oxidative stress plays a critical role in the mobilisation of endothelial progenitor cells (EPCs) from the bone marrow to the circulation. This study was designed to explore the effects of chronic melatonin administration on the promotion of the mobilisation of EPCs and on the preservation of erectile function in type I diabetic rats. Melatonin was administered to streptozotocin-induced type I diabetic rats. EPCs levels were determined using flow cytometry. Oxidative stress in the bone marrow was indicated by the levels of superoxide dismutase and malondialdehyde. Erectile function was evaluated by measuring the intracavernous pressure during an electrostimulation of the cavernous nerve. The density of the endothelium and the proportions of smooth muscle and collagen in the corpus cavernosum were determined by immunohistochemistry. The administration of melatonin increased the superoxide dismutase level and decreased the malondialdehyde level in the bone marrow. This effect was accompanied by an increased level of circulating EPCs in the diabetic rats. The intracavernous pressure to mean arterial pressure ratio of the rats in the treatment group was significantly greater, compared with diabetic control rats. The histological analysis demonstrated an increase in the endothelial density of the corpus cavernosum after the administration of melatonin. However, melatonin treatment did not change the proportions of smooth muscle and collagen in the corpus cavernosum of diabetic rats. Chronic administration of melatonin has a beneficial effect on preventing erectile dysfunction (ED) in type I diabetic rats. Promoting the mobilisation of EPCs is one of the possible mechanisms involved in the improvement of ED. PMID: 22367180 [PubMed - indexed for MEDLINE]
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Related Articles Both immediate and delayed intracavernous injection of autologous adipose-derived stromal vascular fraction enhances recovery of erectile function in a rat model of cavernous nerve injury. Eur Urol. 2012 Oct;62(4):720-7 Authors: Qiu X, Fandel TM, Ferretti L, Albersen M, Orabi H, Zhang H, Lin G, Lin CS, Schroeder T, Lue TF Abstract BACKGROUND: Intracavernous injection of cultured adipose-derived stem cells (ADSCs) effectively restores erectile function in cavernous nerve (CN)-injured rats when administered at the time of injury. However, culturing exposes ADSCs to the risk of contamination and dedifferentiation. OBJECTIVE: Explore the effect of uncultured autologous adipose-derived stromal vascular fraction (SVF) on improving erectile function in a rat model of CN injury when administered at the time of injury or 4 wk after injury. DESIGN, SETTING, AND PARTICIPANTS: Eighty-nine male Sprague Dawley rats were randomly divided into four groups. CN injury or sham surgery was performed at the start of the study, and rats were treated with either SVF or vehicle. Functional testing and histologic analysis were performed 12 wk after CN crush or sham surgery. INTERVENTION: We used intracavernous injection of saline immediately after CN crush (n=23), intracavernous injection of SVF immediately after CN crush (n=17), intracavernous injection of SVF 4 wk after CN crush (n=23), or sham surgery (n=26). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We studied intracavernous pressure (ICP) response to CN electrostimulation and performed histologic examination of midpenile cross-sections. Data were analyzed using one-way analysis of variance followed by the Tukey-Kramer test. RESULTS AND LIMITATIONS: Both immediate and delayed treatment with SVF resulted in a significantly increased ICP-to-mean arterial pressure ratio compared with the vehicle-treated group. Both immediate and delayed treatment with SVF significantly increased expression of neuronal nitric oxide synthase and neurofilament in dorsal penile nerves compared to the vehicle group. Furthermore, the smooth muscle-to-collagen ratio within the corpus cavernosum was significantly improved in both of the SVF groups compared to vehicle-treated rats. The main limitation of the study is the lack of determination of the SVF components. CONCLUSIONS: Uncultured autologous SVF injected immediately or 4 wk after CN crush improved erectile function, promoted nerve regeneration, and prevented fibrosis of the corpus cavernosum following CN injury. PMID: 22397847 [PubMed - indexed for MEDLINE]
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Related Articles Neurotrophic effect of bone marrow mesenchymal stem cells for erectile dysfunction in diabetic rats. Int J Androl. 2012 Aug;35(4):601-7 Authors: Sun C, Lin H, Yu W, Li X, Chen Y, Qiu X, Wang R, Dai Y Abstract It has been demonstrated that intracavernous injection of bone marrow-derived mesenchymal stem cells (BM-MSCs) had beneficial effects on improving erectile function in type-1 diabetic rats. This study was designed to investigate the neurotrophic effect of BM-MSCs for type-1 diabetic rats. Streptozocin-induced type-1 diabetic rats were randomly divided into three groups: diabetic group, BM-MSCs-treated group and BM-MSCs-conditioned medium-treated group. At the 3d, 1 and 2w time points after BM-MSCs injection, three randomly selected rats in MSCs group were sacrificed and penile samples were harvested to detect BM-MSCs in penile tissue. Four weeks after intracavernous injection of BM-MSCs or BM-MSCs-conditioned medium, intracavernous pressure (ICP) was assessed to evaluate the erectile function. Immunohistochemistry was used to track labelled BM-MSCs in penile tissue and to detect neuronal nitric oxide synthase (nNOS) and neurofilament (NF) positive fibres in penile dorsal nerve. Enzyme lined immunosorbent assay (ELISA) was used to measure the concentrations of vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in BM-MSCs-conditioned medium. BM- MSCs secreted detectable levels of VEGF, BDNF and NGF. Intracavernous injection of BM-MSCs improved erectile function in diabetic rats. The functional improvement was accompanied by promoted nNOS and NF positive nerve fibres within penile dorsal nerve in type-1 diabetic rats. Histological data revealed a time-dependent decrease in the number of BM-MSCs in the corpus cavernosum following injection. Furthermore, the beneficial effect of BM-MSCs was partially repeated by BM-MSCs-conditioned medium. Intracavernous injection of BM-MSCs is effective in improving nerve regeneration in diabetic rats. Paracrine effects of BM-MSCs are probably involved in the improvement. PMID: 22428616 [PubMed - indexed for MEDLINE]
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Related Articles Advances in cell-based therapy for peripheral vascular disease. Atherosclerosis. 2012 Aug;223(2):269-77 Authors: Blum A, Balkan W, Hare JM Abstract Evidence is accumulating to support cell-based therapies as a new approach for chronic diseases. Perhaps the area of greatest impact, in terms of patient numbers, is cardiovascular disorders. This review considers cell transplantation as a potential treatment for peripheral vascular disease, including ischemic stroke and erectile dysfunction. Bone marrow derived cells are required for endogenous repair in adult individuals affected by angiopathies. Clinical trials using progenitor cells generated from monocytic or non-monocytic cells indicate that both are effective, suggesting that angiogenesis is the result of cross talk between different cells and pathways. Currently, there are 14 registered clinical trials (ClinicalTrials.gov) examining different approaches to stem cell therapy to cure peripheral artery disease, of which 6 have completed enrollment. Here, we will review published clinical studies that used cell transplantation for peripheral vascular ischemic disorders. PMID: 22494624 [PubMed - indexed for MEDLINE]
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Related Articles Scaffoldless tissue engineering of stem cell derived cavernous tissue for treatment of erectile function. J Sex Med. 2012 Jun;9(6):1522-34 Authors: Orabi H, Lin G, Ferretti L, Lin CS, Lue TF Abstract INTRODUCTION: As one-third of erectile dysfunction (ED) patients do not respond to phosphodiesterase-5 inhibitors, there is great demand for new therapeutic options. Adipose tissue-derived stem cells (ADSCs) represent an ideal source for new ED treatment. AIM: To test if ADSCs can be differentiated into smooth muscle cells (SMCs) and endothelial cells (ECs), if these differentiated cells can be used to engineer cavernous tissue, and if this engineered tissue will remain for long time after implantation and integrate into corporal tissue. METHOD: Rat ADSCs were isolated and differentiated into SMC and ECs. The differentiated cells were labeled with 5-ethynyl-2-deoxyuridine (EdU) and used to construct cavernous tissue. This engineered tissue was implanted in penises of normal rats. The rats were sacrificed after 1 and 2 months; penis and bone marrow were collected to assess cell survival and inclusion in the penile tissues. MAIN OUTCOME MEASURES: The phenotype conversion was checked using morphology, immunocytochemistry (immunohistochemistry [IHC]), and Western blot for SMC and EC markers. The cavernous tissue formation was assessed using rat EC antibody (RECA), calponin, and collagen. The implanted cell survival and incorporation into penis were evaluated with hematoxylin and eosin, Masson's trichrome, and IHC (RECA, calponin, and EdU). RESULTS: The phenotype conversion was confirmed with positive staining for SMC and EC markers and Western blot. The formed tissue exhibited architecture comparable to penile cavernous tissue with SMC and ECs and extracellular matrix formation. The implanted cells survived in significant numbers in the penis after 1 and 2 months. They showed proof of SMC and EC differentiation and incorporation into penile tissue. CONCLUSIONS: The results showed the ability of ADSCs to differentiate into SMC and ECs and form cavernous tissue. The implanted tissue can survive and integrate into the penile tissues. The cavernous tissue made of ADSCs forms new technology for improvement of in vivo stem cell survival and ED treatment. PMID: 22513032 [PubMed - indexed for MEDLINE]
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Related Articles Effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapy-induced erectile dysfunction. J Sex Med. 2012 Jul;9(7):1834-41 Authors: Qiu X, Villalta J, Ferretti L, Fandel TM, Albersen M, Lin G, Dai Y, Lue TF, Lin CS Abstract INTRODUCTION: Radiation therapy (RT) for prostate cancer is frequently associated with posttreatment erectile dysfunction (ED). AIM: To investigate whether injection of adipose-derived stem cells (ADSCs) can ameliorate RT-associated ED. METHODS: Thirty male rats were divided into three groups. The control + phosphate-buffered saline (PBS) group received tail-vein injection of PBS. The radiation + PBS group received radiation over the prostate and tail-vein injection of PBS. The radiation + ADSC group received radiation over the prostate and tail-vein injection of ADSCs, which were labeled with 5-ethynyl-2-deoxyuridine (EdU). Seventeen weeks later, erectile function was evaluated by intracavernous pressure (ICP) in response to electrostimulation of cavernous nerves (CNs). Penile tissue and major pelvic ganglia (MPG) were examined by immunofluorescence (IF) and EdU staining. MAIN OUTCOME MEASURES: Erectile function was measured by ICP. Protein expression was examined by IF, followed by image analysis and quantification. RESULTS: Radiation over the prostate caused a significant decrease in erectile function and in the expression of neuronal nitric oxide synthase (nNOS) in penis and MPG. Cavernous smooth muscle (CSM) but not endothelial content was also reduced. Injection of ADSCs significantly restored erectile function, nNOS expression, and CSM content in the irradiated rats. EdU-positive cells were visible in MPG. CONCLUSIONS: Radiation appears to cause ED via CN injury. ADSC injection can restore erectile function via CN regeneration. PMID: 22548750 [PubMed - indexed for MEDLINE]
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Related Articles Therapeutic effect of adipose-derived stem cells and BDNF-immobilized PLGA membrane in a rat model of cavernous nerve injury. J Sex Med. 2012 Aug;9(8):1968-79 Authors: Piao S, Kim IG, Lee JY, Hong SH, Kim SW, Hwang TK, Oh SH, Lee JH, Ra JC, Lee JY Abstract INTRODUCTION: Cavernous nerve injury is the main reason for post-prostatectomy erectile dysfunction (ED). Stem cell and neuroprotection therapy are promising therapeutic strategy for ED. AIM: To evaluate the therapeutic efficacy of adipose-derived stem cells (ADSCs) and brain-derived neurotrophic factor (BDNF) immobilized Poly-Lactic-Co-Glycolic (PLGA) membrane on the cavernous nerve in a rat model of post-prostatectomy ED. Methods.  Rats were randomly divided into five groups: normal group, bilateral cavernous nerve crush injury (BCNI) group, ADSC (BCNI group with ADSCs on cavernous nerve) group, BDNF-membrane (BCNI group with BDNF/PLGA membrane on cavernous nerve) group, and ADSC/BDNF-membrane (BCNI group with ADSCs covered with BDNF/PLGA membrane on cavernous nerve) group. BDNF was controlled-released for a period of 4 weeks in a BDNF/PLGA porous membrane system. MAIN OUTCOME MEASURES: Four weeks after the operation, erectile function was assessed by detecting the ratio of intra-cavernous pressure (ICP)/mean arterial pressure (MAP). Smooth muscle and collagen content were determined by Masson's trichrome staining. Neuronal nitric oxide synthase (nNOS) expression in the dorsal penile nerve was detected by immunostaining. Phospho-endothelial nitric oxide synthase (eNOS) protein expression and cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum were quantified by Western blotting and cGMP assay, respectively. RESULTS: In the ADSC/BDNF-membrane group, erectile function was significantly elevated, compared with the BCNI and other treated groups. ADSC/BDNF-membrane treatment significantly increased smooth muscle/collagen ratio, nNOS content, phospho-eNOS protein expression, and cGMP level, compared with the BCNI and other treated groups. CONCLUSIONS: ADSCs with BDNF-membrane on the cavernous nerve can improve erectile function in a rat model of post-prostatectomy ED, which may be used as a novel therapy for post-prostatectomy ED. PMID: 22642440 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell therapy for voiding and erectile dysfunction. Nat Rev Urol. 2012 Aug;9(8):435-447 Authors: Vaegler M, Lenis AT, Daum L, Amend B, Stenzl A, Toomey P, Renninger M, Damaser MS, Sievert KD Abstract Voiding dysfunction comprises a variety of disorders, including stress urinary incontinence and overactive bladder, and affects millions of men and women worldwide. Erectile dysfunction (ED) also decreases quality of life for millions of men, as well as for their partners. Advanced age and diabetes are common comorbidities that can exacerbate and negatively impact upon the development of these disorders. Therapies that target the pathophysiology of these conditions to halt progression are not currently available. However, stem cell therapy could fill this therapeutic void. Stem cells can reduce inflammation, prevent fibrosis, promote angiogenesis, recruit endogenous progenitor cells, and differentiate to replace damaged cells. Adult multipotent stem cell therapy, in particular, has shown promise in case reports and preclinical animal studies. Stem cells also have a role in urological tissue engineering for ex vivo construction of bladder wall and urethral tissue (using a patient's own cells) prior to transplantation. More recent studies have focused on bioactive factor secretion and homing of stem cells. In the future, clinicians are likely to utilize allogeneic stem cell sources, intravenous systemic delivery, and ex vivo cell enhancement to treat voiding dysfunction and ED. PMID: 22710667 [PubMed - as supplied by publisher]
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Related Articles Comparative analysis of periprostatic implantation and intracavernosal injection of human adipose tissue-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury. Prostate. 2013 Feb 15;73(3):278-86 Authors: You D, Jang MJ, Lee J, Suh N, Jeong IG, Sohn DW, Kim SW, Ahn TY, Kim CS Abstract BACKGROUND: We compared periprostatic implantation (PPI) and intracavernosal injection (ICI) of human adipose tissue-derived stem cell (ADSC) to facilitate recovery of erectile function in a rat model of cavernous nerve (CN) injury. METHODS: Bilateral CN dissection (BCND) was induced in Sprague-Dawley rats. After BCND 10 rats each were treated with PPI and/or ICI of ADSCs. After 4 weeks erectile responses to electric pelvic ganglion stimulation were studied. Each penis was evaluated in terms of the expression of neuronal nitric oxide synthase and smooth muscle content. RESULTS: The ratio of maximal intracavernosal pressure to mean arterial pressure was significantly decreased in the BCND group (24.5%) compared to the sham group (64.2%). PPI and ICI significantly improved erectile function (46.7% and 47.9%, respectively) compared to the BCND group. A combination of PPI and ICI (42.5%) did not afford any incremental effect on erectile function. After stem cell therapy, the expression of neuronal nitric oxide synthase increased slightly in the ICI group without statistical relevance, whereas the PPI and combination groups showed marginally significant increases (P = 0.08). In both the PPI and ICI groups, the smooth muscle content was similar to the sham group. The combination group showed remarkable increase in smooth muscle content to an extent greater than that seen when either treatment was given alone, although statistically not significant. CONCLUSION: PPI or ICI of ADSCs in a rat model of CN injury were equally effective in recovering penile erection, but may address different types of pathophysiology. PMID: 22821215 [PubMed - indexed for MEDLINE]
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Related Articles Emerging tools for erectile dysfunction: a role for regenerative medicine. Nat Rev Urol. 2012 Sep;9(9):520-36 Authors: Hakim L, Van der Aa F, Bivalacqua TJ, Hedlund P, Albersen M Abstract Erectile dysfunction (ED) is the most common sexual disorder reported by men to their health-care providers and the most investigated male sexual dysfunction. Currently, the treatment of ED focuses on 'symptomatic relief' of ED and, therefore, tends to provide temporary relief rather than providing a cure or reversing the cause. The identification of a large population of "difficult-to-treat" patients has triggered researchers to identify novel treatment approaches, which focus on cure and restoration of the underlying cause of ED. Regenerative medicine has developed extensively in the past few decades and preclinical trials have emphasized the benefit of growth factor therapy, gene transfer, stem cells and tissue engineering for the restoration of erectile function. Development of clinical trials involving immunomodulation in postprostatectomy ED patients and the use of maxi-K channels for gene therapy are illustrative of the advances in the field. However, the search for novel treatment targets and a wealth of preclinical studies represent a dynamic and continuing field of enquiry. PMID: 22824778 [PubMed - indexed for MEDLINE]
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Related Articles Effect of an adipose-derived stem cell and nerve growth factor-incorporated hydrogel on recovery of erectile function in a rat model of cavernous nerve injury. Tissue Eng Part A. 2013 Jan;19(1-2):14-23 Authors: Kim IG, Piao S, Lee JY, Hong SH, Hwang TK, Kim SW, Kim CS, Ra JC, Noh I, Lee JY Abstract Postprostatectomy erectile dysfunction (ED) is the major problem for patients with clinically localized prostate cancer. Recently, gene and stem cell-based therapy of the corpus cavernosum has been attempted for postprostatectomy ED, but those therapies are limited by rapid blood flow and disruption of the normal architecture of the corpus cavernosum. In this study, we attempted to regenerate the damaged cavernous nerve (CN), which is the main cause of ED. We investigated the effectiveness of human adipose-derived stem cell (hADSC) and nerve growth factor-incorporated hyaluronic acid-based hydrogel (NGF-hydrogel) application on the CN in a rat model of bilateral cavernous nerve crush injury. Four weeks after the operation, erectile function was assessed by detecting the intracavernous pressure (ICP)/arterial pressure level by CN electrostimulation. The ICP was significantly increased by application of hADSC with NGF-hydrogel compared to the other experimental groups. CN and penile tissue were collected for histological examination. PKH-26 labeled hADSC colocalized with beta III tubulin were shown in CN tissue sections. hADSC/NGF-hydrogel treatment prevented smooth muscle atrophy in the corpus cavernosum. In addition, the hADSC/NGF-hydrogel group showed increased endothelial nitric oxide synthase protein expression. This study suggests that application of hADSCs with NGF-hydrogel on the CN might be a promising treatment for postprostatectomy ED. PMID: 22834730 [PubMed - indexed for MEDLINE]
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Related Articles [Erectile dysfunction: conservative treatment and new approaches]. Rev Med Brux. 2012 May-Jun;33(3):146-52 Authors: Henriet B, Roumeguère T Abstract Recent societal evolutions have enabled more and more men to talk about erectile dysfunction (ED). There is a strong association between ED and cardiovascular disease and ED should now be considered as an early clinical evidence of vascular disorder. Inhibitors of the PDE-5 have revolutionized the treatment of ED. The three currently drugs (sildenafil, vardenafil and tadalafil) available as first-line therapeutic option, are well tolerated and highly effective in improving erectile function. All the potential cardiac and vascular effects of PDE-5 inhibitors have recently been reviewed. Despite the fact that million patients with ED worldwide have been successfully treated with one of these PDE5 inhibitors, some men are always difficult to treat. Several new PDE-5 inhibitors have recently been developed and are now being investigated in trials. However 30% of patients need alternative therapies and intracavernous injections are the most successful second-line treatment. Some of new therapeutic approaches are currently under investigation such as gene transfer therapy and stem cells therapy, melanocortin activators or extracorporeal shockwave therapy. Such approaches are still at an early stage but remain exciting new targets in difficult to treat patients. PMID: 22891586 [PubMed - indexed for MEDLINE]
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Related Articles Separate or combined treatments with daily sildenafil, molsidomine, or muscle-derived stem cells prevent erectile dysfunction in a rat model of cavernosal nerve damage. J Sex Med. 2012 Nov;9(11):2814-26 Authors: Kovanecz I, Rivera S, Nolazco G, Vernet D, Segura D, Gharib S, Rajfer J, Gonzalez-Cadavid NF Abstract INTRODUCTION: Long-term daily administration of phosphodiesterase type 5 (PDE5) inhibitors in the rat prevents or reverses corporal veno-occlusive dysfunction (CVOD) and smooth muscle cell (CSMC) loss and fibrosis, in both aging and bilateral cavernosal nerve resection (BCNR) models for erectile dysfunction. In the aging rat model, corporal implantation of skeletal muscle-derived stem cells (MDSC) reverses CVOD. Nitric oxide (NO) and cyclic guanosine monophosphate can modulate stem cell lineage. AIM: To investigate in the BCNR model the effects of sildenafil at lower doses, alone or in combination with MDSC or the NO donor molsidomine, on CVOD and the underlying corporal histopathology. MAIN OUTCOMES MEASURES: CVOD, histological, and biochemical markers in rat corporal tissue. Methods.  Rats subjected to BCNR were maintained for 45 days either untreated, or received sildenafil in the water or retrolingually at 10, 2.5, and 1.25 mg/kg/day (medium, low, and very low doses), or intraperitoneal molsidomine, or MDSC implantation into the corpora cavernosa separately or in combination. Cavernosometry evaluated CVOD. Histopathology was assessed on penile sections by Masson trichrome, immunohistochemistry for α-smooth muscle actin (ASMA), or immunofluorescence for neuronal nitric oxide synthase (nNOS)/neurofilament 70, and in fresh tissue by Western blot for various markers and picrosirius red for collagen. RESULTS: All treatments normalized erectile function (drop rate), and most increased the CSMC/collagen ratio and ASMA expression in corporal tissue sections, and reduced collagen content in the penile shaft. MDSC also increased nNOS and brain-derived neurotrophic factor. The combination treatment was not superior to MDSC or sildenafil given alone, and upregulated PDE5. CONCLUSIONS: Lowering the dose of a continuous long-term sildenafil administration still maintained the prevention of CVOD in the BCNR rat previously observed, but it was less effective on the underlying histopathology. As in the aging rat model, MDSC also counteracted CVOD, but supplementation with very low-dose sildenafil did not improve the outcome. PMID: 22974131 [PubMed - indexed for MEDLINE]
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Related Articles Common pitfalls in some of the experimental studies in erectile function and dysfunction: a consensus article. J Sex Med. 2012 Nov;9(11):2770-84 Authors: Cellek S, Bivalacqua TJ, Burnett AL, Chitaley K, Lin CS Abstract INTRODUCTION: Experimental studies investigating physiology of erectile function and pathophysiology erectile dysfunction employ several in vitro and in vivo techniques. As the field of sexual medicine expanding, the proper conduct of such techniques is becoming an even more important necessity than before. AIM: This review article aims to guide scientists, particularly young researchers and new comers in the field, toward employment of these techniques in an appropriate, timely, and competent fashion. METHODS: The authors reviewed the existing available published articles on the following topics: intracavernosal pressure measurements, cavernous nerve injury models, nitric oxide-cyclic guanosine monophosphate pathway, hypertension- and smoking-induced erectile dysfunction models, and stem cells. RESULTS: The authors present a consensus on how to best perform these models and techniques and also highlight the pitfalls. CONCLUSIONS: The authors hope that this article will assist and encourage young scientists in the field and that similar articles covering other important models will be also available to them soon. PMID: 22974227 [PubMed - indexed for MEDLINE]
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Related Articles Intratunical injection of human adipose tissue-derived stem cells prevents fibrosis and is associated with improved erectile function in a rat model of Peyronie's disease. Eur Urol. 2013 Mar;63(3):551-60 Authors: Castiglione F, Hedlund P, Van der Aa F, Bivalacqua TJ, Rigatti P, Van Poppel H, Montorsi F, De Ridder D, Albersen M Abstract BACKGROUND: Peyronie's disease (PD) is a connective tissue disorder of the tunica albuginea (TA). Currently, no gold standard has been developed for the treatment of the disease in its active phase. OBJECTIVE: To test the effects of a local injection of adipose tissue-derived stem cells (ADSCs) in the active phase of a rat model of PD on the subsequent development of fibrosis and elastosis of the TA and underlying erectile tissue. DESIGN, SETTING, AND PARTICIPANTS: A total of 27 male 12-wk-old Sprague-Dawley rats were divided in three equal groups and underwent injection of vehicle (sham), 0.5-μg [corrected] transforming growth factor (TGF)-β1 in a 50-μl vehicle in either a PD or a PD plus ADSC group in the dorsal aspect of the TA. INTERVENTION: The sham and PD groups were treated 1 d after TGF-β1 injection with intralesional treatment of vehicle, and the PD plus ADSC group received 1 million human-labeled ADSCs in the 50-μl vehicle. Five weeks after treatment, six rats per group underwent erectile function measurement. Following euthanasia, penises were harvested for histology and Western blot. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The ratio of intracavernous pressure to mean arterial pressure (ICP/MAP) upon cavernous nerve stimulation, elastin, and collagen III protein expression and histomorphometric analysis of the penis. Statistical analysis was performed by analysis of variance followed by the Tukey-Kramer test for post hoc comparisons or the Mann-Whitney test when applicable. RESULTS AND LIMITATIONS: Erectile function significantly improved after ADSC treatment (ICP/MAP 0.37 in PD vs 0.59 in PD plus ADSC at 5-V stimulation; p=0.03). PD animals developed areas of fibrosis and elastosis with a significant upregulation of collagen III and elastin protein expression. These fibrotic changes were prevented by ADSC treatment. CONCLUSIONS: This study is the first to test stem cell therapy in an animal model of PD. Injection of ADSCs into the TA during the active phase of PD prevents the formation of fibrosis and elastosis in the TA and corpus cavernosum. PMID: 23040209 [PubMed - indexed for MEDLINE]
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Related Articles Intracavernous delivery of freshly isolated stromal vascular fraction rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. J Sex Med. 2012 Dec;9(12):3051-65 Authors: Ryu JK, Tumurbaatar M, Jin HR, Kim WJ, Kwon MH, Piao S, Choi MJ, Yin GN, Song KM, Kang YJ, Koh YJ, Koh GY, Suh JK Abstract INTRODUCTION: Men with diabetic erectile dysfunction (ED) often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. AIM: To examine whether and how freshly isolated stromal vascular fraction (SVF) promotes cavernous endothelial regeneration and restores erectile function in diabetic animals. METHODS: Eight-week-old C57BL/6J mice were used. Diabetes was induced by intraperitoneal injection of streptozotocin. SVF was isolated from epididymal adipose tissues of green fluorescence protein transgenic mice. At 8 weeks after the induction of diabetes, the animals were divided into six groups: controls, diabetic mice, and diabetic mice treated with a single intracavernous injection of phosphate-buffered saline (PBS) or SVF (1 × 10(4) cells, 1 × 10(5) cells, or 2 × 10(5) cells/20 µL, respectively). MAIN OUTCOME MEASURES: Two weeks later, erectile function was measured by cavernous nerve stimulation. The penis was stained with antibodies to CD31, CD34, phosphohistone H3, phospho-endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor-A (VEGF-A). We also performed Western blot for phospho-eNOS and eNOS, and determined cyclic guanosine monophosphate (cGMP) concentration in the corpus cavernosum tissue. RESULTS: Significant improvement in erectile function was noted in diabetic mice treated with SVF at concentrations of 1 × 10(5) and 2 × 10(5) cells, which reached up to 82% of the control values. Local delivery of SVF significantly increased cavernous endothelial cell proliferation, eNOS phosphorylation, and cGMP expression compared with that in the untreated group and the PBS-treated diabetic group. Intracavernous injection of SVF increased cavernous VEGF-A expression and induced recruitment of CD34(+)CD31(-) progenitor cells. Some SVF underwent differentiation into cavernous endothelial cells. SVF-induced promotion of cavernous angiogenesis and erectile function was abolished in the presence of VEGF-Trap, a soluble VEGF-A neutralizing antibody. CONCLUSION: The results support the concept of cavernous endothelial regeneration by use of SVF as a curative therapy for diabetic ED. PMID: 23088258 [PubMed - indexed for MEDLINE]
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Related Articles Periprostatic implantation of human bone marrow-derived mesenchymal stem cells potentiates recovery of erectile function by intracavernosal injection in a rat model of cavernous nerve injury. Urology. 2013 Jan;81(1):104-10 Authors: You D, Jang MJ, Lee J, Jeong IG, Kim HS, Moon KH, Suh N, Kim CS Abstract OBJECTIVE: To evaluate whether periprostatic implantation (PPI) of human bone marrow-derived mesenchymal stem cells (hBMSCs) potentiates recovery of erectile function after intracavernosal injection (ICI) of hBMSCs in a rat model of cavernous nerve (CN) injury. METHODS: Sprague-Dawley rats that had undergone bilateral CN injury were treated by ICI with or without PPI of hBMSCs (10 rats per group). hBMSCs were harvested from healthy human donors. Fibrin scaffolds were used for PPI of hBMSCs. After 4 weeks, erectile responses to electric pelvic ganglion stimulation were studied. The expression of neuronal nitric oxide synthase (nNOS)-positive nerve fibers and smooth muscle/collagen ratio was evaluated in each penis. RESULTS: ICI of hBMSCs slightly improved erectile function compared with the control group (maximal intracavernosal pressure/mean arterial pressure, 39.1% vs 21.7%; P=.060), but a combination of PPI and ICI significantly improved erectile function (45.0%, P=.007). After stem cell therapy, the number of nNOS-positive nerve fibers increased significantly in the PPI+ICI group (P=.017). The smooth muscle/collagen ratio increased significantly after stem cell therapy in the ICI and PPI+ICI groups (both P<.001). CONCLUSION: ICI of hBMSCs in a rat model of CN injury results in recovery of penile erection by decreasing corporeal smooth muscle deterioration and collagen deposition. PPI of hBMSCs potentiates recovery of erectile function by ICI of hBMSCs via regeneration of nNOS-containing nerve fibers. PMID: 23122545 [PubMed - indexed for MEDLINE]
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Related Articles Synergistic effect of mesenchymal stem cells infected with recombinant adenovirus expressing human BDNF on erectile function in a rat model of cavernous nerve injury. Korean J Urol. 2012 Oct;53(10):726-32 Authors: Kim SJ, Choi SW, Hur KJ, Park SH, Sung YC, Ha YS, Cho HJ, Hong SH, Lee JY, Hwang TK, Kim SW Abstract PURPOSE: To evaluate the combined role of mescenchymal stem cells (MSCs) infected with recombinant adenoviruses expressing human BDNF (rAd/hBDNF) on the erectile dysfunction in rat with cavernous nerve injury. MATERIALS AND METHODS: Rats divided into 4 groups: control group, bilateral cavernous nerve crushing group (BCNC group), BCNC with MSCs group and BCNC with MSCs infected with rAd/hBDNF group. After 4-week, functional assessment was done. PKH26 and BDNF staining of major pelvic ganglion and masson's trichrome staining of corpus cavernosum were performed. Western blot analysis of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) was done in corpus cavernosum. RESULTS: After 4 weeks, BCNC with MSCs and MSCs infected with rAd/hBDNF groups showed significantly well-preserved erectile function compared with BCNC group. Moreover, the erectile function of MSCs infected with rAd/hBDNF group was significantly well-preserved than BCNC with MSCs group. The smooth muscle of corpus cavernosum was significantly preserved in BCNC with MSCs and MSCs infected with rAd/hBDNF groups compared with BCNC group. More preservation of smooth muscle was observed in rats with MSCs infected with rAd/hBDNF than with MSCs alone. Significant increase expression of eNOS and nNOS was noted in rats with MSCs infected with rAd/hBDNF than with MSCs alone. CONCLUSIONS: The erectile function was more preserved after injection with MSCs infected with rAd/hBDNF in rat with ED caused by cavernous nerve injury. Therefore, the use of MSC infected with rAd/hBDNF may have a better treatment effect on ED cause by cavernous nerve injury. PMID: 23136635 [PubMed]
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Related Articles Adipose-derived stem cells for the treatment of Peyronie's disease? Eur Urol. 2013 Mar;63(3):561-2 Authors: Lin CS, Lue TF PMID: 23149148 [PubMed - indexed for MEDLINE]
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Related Articles Sexual dysfunction: The potential of stem cell therapy for Peyronie disease. Nat Rev Urol. 2013 Jan;10(1):8-9 Authors: Shindel AW PMID: 23165398 [PubMed - indexed for MEDLINE]
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Related Articles [Stem cell therapy for erectile dysfunction]. Zhonghua Nan Ke Xue. 2012 Sep;18(9):827-30 Authors: Wang ML, Song LJ, Lu HK Abstract Erectile dysfunction (ED), as a pathological phenomenon, refers to repeated or sustained difficulty to achieve and maintain sufficient penile erection to complete satisfactory sexual intercourse or sexual activity in male. The erectile reflex interruption induced by cavernous nerve (CN) damage is a direct cause of ED. In addition, the apoptosis of smooth muscle cells and endothelial cells in the corpus cavernosum caused by CN injury, along with the reduction of corpus cavernosum smooth muscle fibers, can increase the incidence of ED. Therefore, early intervention of the pathological process of CN injury and promotion of CN regeneration are essential for the treatment of ED. In recent years, the stem cell therapy for ED has become a focus in clinical research. This article offers an overview on the application of embryonic stem cells, mesenchymal stem cells, muscle-derived stem cells, and adipose stem cells in the treatment of ED. PMID: 23193673 [PubMed - indexed for MEDLINE]
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Related Articles Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med. 2013 Mar;10(3):738-46 Authors: Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, Lin CS Abstract Introduction.  Low-energy shockwave therapy (LESWT) has been shown to improve erectile function in patients suffering from diabetes mellitus (DM)-associated erectile dysfunction (ED). However, the underlying mechanism remains unknown. Aim.  The aim of this study is to investigate whether LESWT can ameliorate DM-associated ED in a rat model and examine the associated changes in the erectile tissues. Methods.  Newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous mesenchymal stem cells (MSCs). Eight weeks later, eight of these rats were randomly chosen to serve as normal control (N group). The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce DM. Eight of these rats were randomly chosen to serve as DM control (DM group), whereas another eight rats were subject to shockwave (SW) treatment (DM+SW group). Each rat in the DM+SW group received 300 shocks at energy level of 0.1 mJ/mm(2) and frequency of 120/minute. This procedure was repeated three times a week for 2 weeks. Another 2 weeks later, all 24 rats were evaluated for erectile function by intracavernous pressure (ICP) measurement. Afterward, their penile tissues were examined by histology. Main Outcome Measures.  Erectile function was measured by ICP. Neuronal nitric oxide synthase (nNOS)-positive nerves and the endothelium were examined by immunofluorescence staining. Smooth muscle and MSCs were examined by phalloidin and EdU staining, respectively. Results.  STZ treatment caused a significant decrease in erectile function and in the number of nNOS-positive nerves and in endothelial and smooth muscle contents. These DM-associated deficits were all partially but significantly reversed by LESWT. MSCs (EdU-positive cells) were significantly more numerous in DM+SW than in DM rats. Conclusion.  LESWT can partially ameliorate DM-associated ED by promoting regeneration of nNOS-positive nerves, endothelium, and smooth muscle in the penis. These beneficial effects appear to be mediated by recruitment of endogenous MSCs. Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, and Lin C-S. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med 2013;10:738-746. PMID: 23253086 [PubMed - indexed for MEDLINE]
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Related Articles Reply from Authors re: Ching-Shwun Lin, Tom F. Lue. Adipose-derived Stem Cells for the Treatment of Peyronie's Disease? Eur Urol 2013;63:561-2: Xenogeneic Adipose Stem Cell Treatment in a Rat Model of Peyronie's Disease. Eur Urol. 2013 Mar;63(3):563-4 Authors: Castiglione F, Hedlund P, Van der Aa F, Bivalacqua TJ, Rigatti P, Van Poppel H, Montorsi F, De Ridder D, Albersen M PMID: 23265388 [PubMed - indexed for MEDLINE]
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Related Articles Effect of mesenchymal stem cells associated to matrixen on the erectile function in the rat model with bilateral cavernous nerve crushing injury. Int Braz J Urol. 2012 Nov-Dec;38(6):833-41 Authors: Kim SJ, Park SH, Sung YC, Kim SW Abstract OBJECTIVES: To evaluate the effect of mesenchymal stem cells (MSCs) and MSCs mixed with Matrixen as a cell carrier on the erectile dysfunction caused by bilateral cavernous nerve crushing injury. MATERIALS AND METHODS: White male Sprague-Dawley rats were divided into 4 groups: sham-operated control group (n = 5), bilateral cavernous nerve crushing group (BCNC group, n = 10), BCNC administered with MSCs group (n = 10,1x106 in 20 µL), BCNC administered with Matrixen group (n = 10.1x106 in 20 µL), BCNC administered with MSCs/Matrixen group (n = 10.1x106 in 20 µL). After functional assessment at 4 weeks, major pelvic ganglion (MPG) and penile tissue were collected. Immunofluorescent staining of MPG was performed with PKH26 and Tuj1. Western blot analysis of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) were done in corpus cavernosum. RESULTS: ICP/MAP ratios of BCNC with MSCs and MSCs/Matrixen groups were significantly increased compared with BCNC and BCNC with Matrixen group. Moreover, ICP/MAP ratios of MSCs/Matrixen group were significantly increased compared with BCNC with MSCs group. In MPG, the more implantation of MSCs and increased expression of nerve cells were observed in MSCs/Matrixen group compared with BCNC with MSCs group. Significant increase expression of eNOS and nNOS was also noted in BCNC with MSCs/Matrixen group. CONCLUSION: The erectile function was more preserved in MSCs/Matrixen group compared with the administration of MSCs alone in the rats with bilateral cavernous nerve crushing injury. Therefore, we consider that the use of transplant cell carrier such as Matrixen may help the implantation of MSCs and improve the therapeutic effect of MSCs. PMID: 23302404 [PubMed - indexed for MEDLINE]
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Related Articles Isolation and characterization of novel, highly proliferative human CD34/CD73-double-positive testis-derived stem cells for cell therapy. Stem Cells Dev. 2013 Aug 1;22(15):2158-73 Authors: Choi WY, Jeon HG, Chung Y, Lim JJ, Shin DH, Kim JM, Ki BS, Song SH, Choi SJ, Park KH, Shim SH, Moon J, Jung SJ, Kang HM, Park S, Chung HM, Ko JJ, Cha KY, Yoon TK, Kim H, Lee DR Abstract Human adult stem cells are a readily available multipotent cell source that can be used in regenerative medicine. Despite many advantages, including low tumorigenicity, their rapid senescence and limited plasticity have curtailed their use in cell-based therapies. In this study, we isolated CD34/CD73-double-positive (CD34(+)/CD73(+)) testicular stromal cells (HTSCs) and found that the expression of CD34 was closely related to the cells' stemness and proliferation. The CD34(+)/CD73(+) cells grew in vitro for an extended period of time, yielding a multitude of cells (5.6×10(16) cells) without forming tumors in vivo. They also differentiated into all three germ layer lineages both in vitro and in vivo, produced cartilage more efficiently compared to bone marrow stem cells and, importantly, restored erectile function in a cavernous nerve crush injury rat model. Thus, these HTSCs may represent a promising new autologous cell source for clinical use. PMID: 23509942 [PubMed - indexed for MEDLINE]
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Related Articles Combined therapeutic effect of udenafil and adipose-derived stem cell (ADSC)/brain-derived neurotrophic factor (BDNF)-membrane system in a rat model of cavernous nerve injury. Urology. 2013 May;81(5):1108.e7-14 Authors: Jeong HH, Piao S, Ha JN, Kim IG, Oh SH, Lee JH, Cho HJ, Hong SH, Kim SW, Lee JY Abstract OBJECTIVE: To prevent cavernous nerve injury and corpus cavernosum apoptosis-induced erectile dysfunction (ED) after prostatectomy surgery, we investigated whether oral administration of udenafil combination with covering adipose-derived stem cells (ADSCs) and brain-derived neurotrophic factor (BDNF) immobilized poly-lactic-co-glycolic (PLGA) membrane on the injured cavernous nerve could further improve erectile dysfunction. METHODS: Adult Sprague-Dawley rats were divided into 5 groups: normal group (sham-operated group), bilateral cavernous nerve injury (BCNI) group (BCNI group), udenafil group (oral administration of udenafil 20 mg/kg daily), AB group (BCNI group with ADSCs covered with BDNF membrane on cavernous nerve), AB/udenafil group (AB group with udenafil group). After 4 weeks, erectile function was examined before tissue harvest. Penile tissues were evaluated in terms of the expression of smooth muscle actin (SMA), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF). The cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum was quantified by cGMP assay. RESULTS: AB/udenafil treatment markedly improved erectile function and prevented the architecture damage of the corpus cavernosum, compared with other treated groups. Udenafil had no statistical significance on increasing nNOS expression, but enhanced VEGF expression. On the contrary, the AB group had no statistical significance on enhancing VEGF expression, but increased nNOS expression. AB/udenafil treatment significantly increased nNOS expression, VEGF expression, and elevated cGMP level, compared with the udenafil group and AB group. CONCLUSION: The orally administered udenafil combination with ADSC/BDNF-membrane system protected cavernous nerve and improved angiogenesis in the corpus cavernosum, which further maintained erectile function in a rat model of postprostatectomy erectile dysfunction. PMID: 23522997 [PubMed - indexed for MEDLINE]
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Related Articles Polycythemia vera revealed via a bladder tumor in a patient with erectile dysfunction: a case report. J Med Case Rep. 2013;7:85 Authors: Bouchikhi AA, Tazi MF, Mellas S, Amiroune D, Elammari JE, Khallouk A, El Fassi MJ, Farih MH Abstract INTRODUCTION: Polycythemia vera is a polyglobular myeloproliferative syndrome related to the mutation of multipotent hemopoietic stem cells. This case report describes a patient whose bladder tumor was associated with polycythemia vera and erectile dysfunction. The association of bladder neoplasia with polycythemia vera and erectile dysfunction has not previously been reported in the literature. CASE PRESENTATION: A 40-year-old Moroccan man was followed up for a bladder tumor which manifested with coagulant hematuria and a facial erythrosis with a hemoglobin level of 20.3g/L suggesting polycythemia vera. The patient also suffered from an erectile disorder. Considering the anesthesia difficulty due to polyglobulia, the patient was treated by bleeding. This treatment enabled the patient's sexual performance to be improved and adjustment of his hemoglobin to a level allowing anesthesia, and hence surgical resection of his bladder tumor. CONCLUSION: Erectile dysfunction associated with polycythemia vera is elucidated by rheological disorders. Bleeding contributed to satisfactory sexual performance and facilitated treatment of polycythemia vera because it enabled anesthesia to be performed and hence the surgical resection of the bladder tumor. PMID: 23537044 [PubMed]
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Related Articles Sildenafil and cardioprotection. Curr Pharm Des. 2013;19(39):6842-7 Authors: Kukreja RC Abstract The phosphodiesterese-5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), tadalafil (Cialis™) and avanafil (Stendra™) have been developed for the treatment of erectile dysfunction. Moreover, sildenafil and tadalafil have been approved for the management of pulmonary arterial hypertension. A number of preclinical studies have shown that PDE5 inhibitors have powerful protective effect against several clinical scenarios including myocardial ischemia/reperfusion injury, doxorubicin and post-MI, heart failure, cardiac hypertrophy, heart transplantation, Duchenne muscular dystrophy and preconditioning of stem cells. Based on these studies, it appears that sildenafil and other PDE5 inhibitors hold promise for further development as novel drug therapies in cardioprotection. PMID: 23590161 [PubMed - indexed for MEDLINE]
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Related Articles Therapeutic angiogenesis as a potential future treatment strategy for erectile dysfunction. World J Mens Health. 2012 Aug;30(2):93-8 Authors: Ryu JK, Suh JK Abstract The cavernous endothelium plays a crucial role in regulating the tone of the underlying smooth muscle and physiologic penile erection. Recently, the link between erectile dysfunction (ED) and cardiovascular disease was unveiled, and the main etiology of ED was found to be vasculogenic. Although oral phosphodiesterase-5 inhibitors are generally effective for men with ED, such therapies do not cure underlying vasculopathy in the corpus cavernosum tissue. This review addresses current preclinical protein, gene, and cell or stem cell therapies for enhancing cavernous endothelial regeneration and restoring erectile function. PMID: 23596595 [PubMed]
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Related Articles Transplantation KCNMA1 modified bone marrow-mesenchymal stem cell therapy for diabetes mellitus-induced erectile dysfunction. Andrologia. 2014 Jun;46(5):479-86 Authors: He Y, He W, Qin G, Luo J, Xiao M Abstract This study assessed the effect of KCNMA1 transfected bone marrow-mesenchymal stem cells (BM-MSCs) on the improvement of erectile function in diabetic rats. Sixty male Sprague-Dawley rats were injected with streptozotocin (STZ) and screened with apomorphine (APO) to establish diabetes mellitus-induced erectile dysfunction (DMED). DMED rats were randomly divided into four groups: rats in each group underwent intracavernous injection with either phosphate buffer solution (DMED+PBS), nontransfected MSCs (DMED+MSCs), empty vector transfected MSCs (DMED+null-MSCs) or KCNMA1 transfected MSCs (DMED+KCNMA1-MSCs). Before injection, high levels of KCNMA1 expression were confirmed in KCNMA1-MSCs using RT-PCR and Western blotting. The lentivirus transfected MSCs maintained their potential for multidirectional differentiation. Four weeks after injection, erectile function was ascertained by measuring intracavernous pressure (ICP). Penile tissues were collected for immunohistochemical analysis. The expression of KCNMA1 in the corpus cavernosum was increased, and the DMED+KCNMA1-MSCs group displayed a significant improvement of erectile function. We concluded that KCNMA1 was able to enhance the positive effect of MSCs in the treatment of diabetes-associated erectile dysfunction. PMID: 23646921 [PubMed - in process]
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Related Articles Vascular regenerative therapies for the treatment of erectile dysfunction: current approaches. Andrology. 2013 Jul;1(4):533-40 Authors: Condorelli RA, Calogero AE, Vicari E, Favilla V, Morgia G, Cimino S, La Vignera S Abstract The pharmacological treatment of erectile dysfunction (ED) is mainly represented by the administration of inhibitors of phosphodiesterase-5 (PDE5). However, in the clinical practice many patients do not benefit from such a treatment, hence the scientific interest extends to other therapeutic strategies; in particular, to the vascular regenerative therapy. This review describes the main acquisitions related to this approach represented by the mesenchymal stem cell or adipose tissue stem cell transplantation and endothelial nitric oxide synthase or vascular endothelial growth factor gene therapy. Moreover, there are other two aspects of wide interest represented by the potential vascular regenerative effects exerted by the PDE5 inhibitors and the therapeutic strategies for a category of patients who more frequently do not respond to the conventional treatment for ED, the patients with diabetes mellitus. PMID: 23658196 [PubMed - indexed for MEDLINE]
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Related Articles [Application of adipose-derived stem cells in lower urinary tract reconstruction]. Zhonghua Nan Ke Xue. 2013 Apr;19(4):365-9 Authors: Zhou Z, Zhang M, Lu MJ Abstract Adipose-derived stem cells have self-renewal and multi-differentiation potentials, which can differentiate into smooth muscle cells, urinary epithelial-like cells, endothelial cells, neuron-like cells, etc. and secrete a variety of growth factors. As a result, the research on adipose-derived stem cells in lower urinary tract reconstruction using tissue engineering has been a highlight in recent years. This review focuses on the application of adipose-derived stem cells as seed cells to lower urinary tract reconstruction by tissue engineering in such diseases as bladder defect, stress urinary incontinence, and erectile dysfunction. PMID: 23678720 [PubMed - indexed for MEDLINE]
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Related Articles Imatinib mesylate (Gleevec) induces human corpus cavernosum relaxation by inhibiting receptor tyrosine kinases (RTKs): identification of new RTK targets. Urology. 2013 Sep;82(3):745.e11-6 Authors: Gur S, Sikka SC, Abdel-Mageed AB, Abd Elmageed ZY, Rezk B, Pankey E, Kadowitz PJ, Hellstrom WJ Abstract OBJECTIVE: To evaluate the effect of the tyrosine kinase inhibitor imatinib mesylate (Gleevec) on human corpus cavernosum (HCC) smooth muscle tone. METHODS: HCC were obtained from 18 erectile dysfunction (ED) patients undergoing penile prosthesis surgery. The effects of imatinib in HCC strips were investigated in the presence of various inhibitors. The human phosphoreceptor protein tyrosine kinase (PTK) array (Proteome Profiler Array) detected changes in receptor phosphorylation before and after imatinib. Immunohistochemistry was used to localize phosphorylated c-kit (CD117/stem cell factor) in HCC smooth muscle cells. RESULTS: Phenylephrine-induced contraction in HCC was significantly inhibited by imatinib (97.7% ± 2.3%). l-nitro-arginine methyl ester (l-NAME) or guanylyl cyclase inhibitor [1H-1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) alone did not reverse the effect of imatinib, but suppressed this response in combination (18.0% ± 0.6%). The K(+) channel blockers (apamin and tetraethyl ammonium) decreased the imatinib-induced relaxation by 64% and 51%, respectively. PTK microarray analysis of 42 different phospho-receptor tyrosine kinases showed 14 were clearly activated in HCC. Imatinib treatment significantly inhibited phosphorylation of PTKs. A high level of CD117/c-kit-positive immunostaining was detected in untreated HCC smooth muscle, but not in treated HCC. CONCLUSION: Imatinib caused HCC smooth muscle relaxation in vitro mediated by nitric oxide/guanosine monophosphate signaling, involving the large-conductance Ca(2+)-activated K(+)-channels (BK(Ca)) or by inhibiting the upregulated PTK pathway. These results suggest that imatinib may also benefit erectile dysfunction patients who are not responsive to phosphodiesterase-5 inhibitors. PMID: 23856589 [PubMed - indexed for MEDLINE]
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Related Articles Expression of a Distinct Set of Chemokine Receptors in Adipose Tissue-Derived Stem Cells is Responsible for In Vitro Migration Toward Chemokines Appearing in the Major Pelvic Ganglion Following Cavernous Nerve Injury. Sex Med. 2013 Aug;1(1):3-15 Authors: Albersen M, Berkers J, Dekoninck P, Deprest J, Lue TF, Hedlund P, Lin CS, Bivalacqua TJ, Van Poppel H, De Ridder D, Van der Aa F Abstract INTRODUCTION: Adipose tissue-derived stem cells (ADSCs) herald tremendous promise for clinical application in a wide range of injuries and diseases. Several preclinical reports demonstrate their efficacy in the treatment of cavernous nerve (CN) injury-induced erectile dysfunction in rats. It was recently illustrated that these effects were established as a result of ADSC migration to the major pelvic ganglion (MPG) where these cells induced neuroregeneration in loco. AIMS: The study aims to identify chemotactic factors in the MPG following injury and to match upregulated chemokines to their respective receptors in human ADSC on the genomic, structural, and functional levels. METHODS: Quantitative real-time polymerase chain reaction, fluorescence-activated cell sorting (FACS), intracellular FACS, immunofluorescence microscopy, migration assays, and calcium imaging were used in this study. MAIN OUTCOME MEASURES: The main outcomes are chemokine expression in the MPG following CN injury, and the functional and structural presence of chemokine receptors in ADSC. RESULTS: CCR4, CX3CR1, and XCR1 are functionally and structurally present in human ADSC, and are activated by the chemokines CCL2, CX3CL1, and XCL1 respectively, which are upregulated in the MPG following CN injury. CXCR4 and its ligand CXCL12 (SDF1) are likely no major homing factors for ADSC. Expression of chemokine receptor mRNA in ADSC did not necessarily translate into receptor presence at the cell surface and/or functional activation of these receptors. Most of the expressed chemokine receptors were detected in the intracellular compartment of these cells. CONCLUSIONS: We identified the ligand/chemokine receptor pairs CCL2/CCR4, CX3CL1/CX3CR1, and XCL1/XCR1 as potentially responsible for ADSC homing toward the MPG following CN injury. The intracellular localization of various chemokine receptors likely indicates redirecting of chemokine receptors to the cell surface under specific cellular conditions. Furthermore, modification of expression of these receptors at the genomic level may potentially lead to improved migration toward injury sites and thus enhancement of treatment efficacy. Albersen M, Berkers J, Dekoninck P, Deprest J, Lue TF, Hedlund P, Lin C-S, Bivalacqua TJ, Van Poppel H, De Ridder D, and Van der Aa F. Expression of a distinct set of chemokine receptors in adipose tissue-derived stem cells is responsible for in vitro migration toward chemokines appearing in the major pelvic ganglion following cavernous nerve injury. Sex Med 2013;1:3-15. PMID: 25356281 [PubMed]
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Related Articles Genital chronic GVHD in men after hematopoietic stem cell transplantation: a single-center cross-sectional analysis of 155 patients. Biol Blood Marrow Transplant. 2013 Nov;19(11):1574-80 Authors: Mueller SM, Haeusermann P, Rovó A, Halter JP, Passweg J, Itin P, Tichelli A Abstract We assessed the prevalence and clinical features of genital skin changes in men after allogeneic hematopoietic stem cell transplantation (HSCT) and evaluated the correlation between genital chronic graft-versus-host disease (cGVHD) and other manifestations of cGVHD as well as sexual issues. In a cross-sectional cohort study, 155 male recipients alive 1 year or more after HSCT were assessed during their annual follow-up evaluation. Correlation between genital skin changes and other cGVHD manifestations was evaluated, and post-transplantation sexual contentment and sexual functioning were assessed by 2 self-assessment questionnaires, including the 5-item version of the International Index of Erectile Function (IIEF-5) and the modified Brief Sexual Symptom Checklist (mBSSC). Median time between HSCT and genital examination was 5.9 years (range, 1 to 30.3 years). Thirty-one of 155 patients (20%) presented with genital skin changes. Twenty-one of those (13%) presented clinically inflammatory genital skin changes considered as genital cGVHD: 12 had inflammatory (noninfectious) balanoposthitis, 6 had lichen sclerosis-like lesions, 5 had phimosis, and 2 patients had more than 1 feature. Patients with inflammatory genital skin changes had a significantly higher coincidence of oral (P < .0001), ocular (P < .002), and/or cutaneous cGVHD (P < .026) when compared with patients without genital lesions. The rate of IIEF-5 questionnaire response was 59% (91 of 155). Among them, 67% reported erectile dysfunction. Erectile dysfunction was significantly more frequent in patients with genital cGVHD (P = .0075). Seventy-five of 155 patients (48%) answered the mBSSC questionnaire. Only 40% of them reported sexual contentment. Genital skin changes in male recipients after allogeneic HSCT are frequent and seem to be an under-reported relevant late effect. Inflammatory genital skin changes can be considered as a form of genital cGVHD often associated with manifestations of extragenital mucocutaneous cGVHD. PMID: 23962394 [PubMed - indexed for MEDLINE]
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Related Articles Correction of diabetic erectile dysfunction with adipose derived stem cells modified with the vascular endothelial growth factor gene in a rodent diabetic model. PLoS One. 2013;8(8):e72790 Authors: Liu G, Sun X, Bian J, Wu R, Guan X, Ouyang B, Huang Y, Xiao H, Luo D, Atala A, Zhang Y, Deng C Abstract The aim of this study was to determine whether adipose derived stem cells (ADSCs) expressing vascular endothelial growth factor (VEGF) gene can improve endothelial function, recover the impaired VEGF signaling pathway and enhance smooth muscle contents in a rat diabetic erectile dysfunction (DED) model. DED rats were induced via intraperitoneal injection of streptozotocin (40 mg/kg), and then screened by apomorphine (100 µg/kg). Five groups were used (n = 12/group)-Group 1 (G1): intracavernous injection of lentivirus-VEGF; G2: ADSCs injection; G3: VEGF-expressing ADSCs injection; G4: Phosphate buffered saline injection; G1-G4 were DED rats; G5: normal rats. The mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured at days 7 and 28 after the injections. The components of the VEGF system, endothelial, smooth muscle, pericytes markers in cavernoursal tissue were assessed. On day 28 after injection, the group with intracavernosum injection of ADSCs expressing VEGF displayed more efficiently and significantly raised ICP and ICP/MAP (p<0.01) than those with ADSCs or lentivirus-VEGF injection. Western blot and immunofluorescent analysis demonstrated that improved erectile function by ADSCs-VEGF was associated with increased expression of endothelial markers (VEGF, VEGF R1, VEGF R2, eNOS, CD31 and vWF), smooth muscle markers (a-actin and smoothelin), and pericyte markers (CD146 and NG2). ADSCs expressing VEGF produced a therapeutic effect and restored erectile function in diabetic rats by enhancing VEGF-stimulated endothelial function and increasing the contents of smooth muscle and pericytes. PMID: 24023647 [PubMed - indexed for MEDLINE]
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Related Articles Stem-cell therapy for erectile dysfunction. Expert Opin Biol Ther. 2013 Nov;13(11):1585-97 Authors: Lin CS, Xin Z, Dai J, Huang YC, Lue TF Abstract INTRODUCTION: Stem cells (SCs) have been investigated for the treatment of erectile dysfunction (ED). AREAS COVERED: This review covers key disease targets and all 33 preclinical studies, including their use of SC types, animal models, transplantation routes, and outcome assessment methods. EXPERT OPINION: In the past one and half years there have been more stem-cell-for-erectile-dysfunction studies than the prior 8 years combined. These new studies tend to use combinatory treatment approaches by modifying or supplementing SCs with angiogenic or neurotrophic genes or proteins. However, when considering all risks and benefits, these combinatory approaches do not seem more advantageous than single-SC approaches. Another trend is the choice of transplantation routes other than the standard intracavernous (IC) injection. However, with the exception of intravenous injection, these new transplantation approaches are more cumbersome than IC injection and yet offer no evidence of producing better outcomes. In contrast to these variations, a consensus among these studies is the suggestion that paracrine action, as opposed to cellular differentiation, is the principal therapeutic mechanism. In conclusion, IC injection of a single SC type should be the choice protocol for initial clinical trials, and this is clearly the case with two clinical trials that are currently recruiting patients. PMID: 24090162 [PubMed - indexed for MEDLINE]
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Related Articles [Stem cell therapy and tissue engineering in regenerative urology]. Urologe A. 2013 Dec;52(12):1671-8 Authors: Vaegler M, Amend B, Aicher W, Stenzl A, Sievert KD Abstract BACKGROUND: So far there is no clinically established, effective tissue engineering therapy for dysfunction or defects of the lower urinary tract. The concentration of experimental data, initial clinical studies and individual case reports underlines that stem cell treatment for bladder storage and voiding problems, erectile dysfunction and other urothelial defects of the lower urinary tract could close the gap between individualized therapy and potential biomedical applications. RESULTS: As a result of fundamental research work over the last decade a characterization of various stem cell populations and evaluation of different urological therapy options could be performed. Thereby, aspects of optimal administration, migration, secretion of bioactive factors and stage of differentiation of stem cells with respect to an improved efficiency of treatment were investigated. Because successful tissue regeneration depends on angiogenesis and innervation, particular attention was paid to these important factors. CONCLUSIONS: Various clinical indications for stem cell treatment and tissue reconstruction that may be required after radical prostatectomy, such as stress urinary incontinence, urethral reconstruction and erectile dysfunction have materialized and are currently being verified in preclinical studies and phase I trials. PMID: 24166059 [PubMed - indexed for MEDLINE]
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Related Articles Isolation and passage of muscle-derived stem cells from the rat penile corpora cavernosa and induction of differentiation into smooth muscle cells. Cytotechnology. 2014 Dec;66(6):987-94 Authors: Xu LJ, Xue BX, Chen D, Gao J, Yang DR, Sun CY, Cui Y, Shan YX Abstract This study treated the isolation and passage of muscle-derived stem cells (MDSCs) from rat penile corpora cavernosa, detection of stem cell marker expression, observation of their self-renewal and continuous proliferation, and demonstration of their potential to differentiate into smooth muscle cells in co-culture. Muscle-derived stem cells from the rat penile corpora cavernosa were isolated and purified. The expression of stem cell markers Sca-1 and desmin was detected in PP6 cells, thus confirming that the main components of PP6 cells are MDSCs. The expression of Sca-1 and desmin occurred both in PP6 cells and cells at passages 3, 6, and 8, and there was no significant decrease in the expression level with increasing passage number. The growth curves indicated that the cell doubling time was approximately 48 h. The cells entered the stationary phase after approximately 7 days of culture. The proliferative activity of the cells at passage 8 remained unchanged. After 2 days of co-culture with smooth muscle cells, the DAPI-labeled MDSCs tended to exhibit smooth muscle cell morphology and expression of α-SMA was detected. MDSCs exist in the rat penile corpora cavernosa and possess the potential to differentiate into smooth muscle cells. This discovery serves as the basis in view of the potential use of endogenous stem cells for the treatment of erectile dysfunction (ED). PMID: 24242826 [PubMed]
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Related Articles Intracavernous delivery of clonal mesenchymal stem cells restores erectile function in a mouse model of cavernous nerve injury. J Sex Med. 2014 Feb;11(2):411-23 Authors: Ryu JK, Kim DH, Song KM, Yi T, Suh JK, Song SU Abstract INTRODUCTION: Recently, much attention has focused on stem cell therapy; bone marrow-derived stem cells (BMSCs) are one of the most studied mesenchymal stem cells used in the field of erectile dysfunction (ED). However, a major limitation for the clinical application of stem cell therapy is the heterogeneous nature of the isolated cells, which may cause different treatment outcomes. AIM: We investigated the effectiveness of mouse clonal BMSCs obtained from a single colony by using subfractionation culturing method (SCM) for erectile function in a mouse model of cavernous nerve injury (CNI). METHODS: Twelve-week-old C57BL/6J mice were divided into four groups: sham operation group, bilateral CNI group receiving a single intracavernous (IC) injection of phosphate-buffered saline (20 μL) or clonal BMSCs (3 × 10(5) cells/20 μL), and receiving a single intraperitoneal (IP) injection of clonal BMSCs (3 × 10(5) cells/20 μL). MAIN OUTCOME MEASURES: The clonal BMSC line was analyzed for cell-surface epitopes by using fluorescence-activated cell sorting and for differentiation potential. Two weeks after CNI and treatment, erectile function was measured by electrically stimulating the cavernous nerve. The penis was harvested for histologic examinations and Western blot analysis. RESULTS: Clonal BMSCs expressed cell surface markers for mesenchymal stem cells and were capable of differentiating into several lineages, including adipogenic, osteogenic, and chondrogenic cells. Both IC and IP injections of clonal BMSCs significantly restored cavernous endothelial and smooth muscle content, and penile nNOS and neurofilament content in CNI mice. IC injection of clonal BMSCs induced significant recovery of erectile function, which reached 90-100% of the sham control values, whereas IP injection of clonal BMSCs partially restored erectile function. CONCLUSION: We established a homogeneous population of mouse clonal BMSCs using SCM; clonal BMSCs successfully restored erectile function in CNI mice. The homogeneous nature of clonal mesenchymal stem cells may allow their clinical applications. PMID: 24251583 [PubMed - indexed for MEDLINE]
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Related Articles Oral Bisphenol A (BPA) given to rats at moderate doses is associated with erectile dysfunction, cavernosal lipofibrosis and alterations of global gene transcription. Int J Impot Res. 2014 Mar-Apr;26(2):67-75 Authors: Kovanecz I, Gelfand R, Masouminia M, Gharib S, Segura D, Vernet D, Rajfer J, Li DK, Kannan K, Gonzalez-Cadavid NF Abstract Bisphenol A (BPA), a suspected reproductive biohazard and endocrine disruptor, released from plastics is associated with ED in occupationally exposed workers. However, in rats, despite the induction of hypogonadism, apoptosis of the penile corporal smooth muscle (SM), fat infiltration into the cavernosal tissue and changes in global gene expression with the intraperitoneal administration of high dose BPA, ED was not observed. We investigated whether BPA administered orally rather than intraperitoneally to rats for longer periods and lower doses will lead to ED. Main outcome measures are ED, histological, and biochemical markers in rat penile tissues. In all, 2.5-month-old rats were given drinking water daily without and with BPA at 1 and 0.1 mg kg(-1) per day. Two months later, erectile function was determined by cavernosometry and electrical field stimulation (EFS) and serum levels of testosterone (T), estradiol (E2) and BPA were measured. Penile tissue sections were assayed by Masson (SM/collagen), Oil Red O (fat), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) (apoptosis), immunohistochemistry for Oct4 (stem cells), and α-SM actin/calponin (SM and myofibroblasts), applying quantitative image analysis. Other markers were assayed by western blotting. DNA microarrays/microRNA (miR) assays defined transcription profiles. Orally administered BPA did not affect body weight, but (1) decreased serum T and E2; (2) reduced the EFS response and increased the drop rate; (3) increased within the corporal tissue the presence of fat, myofibroblasts and apoptosis; (4) lowered the contents of SM and stem cells, but not nerve terminals; and (5) caused alterations in the transcriptional profiles for both mRNA and miRs within the penile shaft. Long-term exposure of rats to oral BPA caused a moderate corporal veno-occlusive dysfunction (CVOD), possibly due to alterations within the corporal tissue that pose gene transcriptional changes related to inflammation, fibrosis and epithelial/mesenchymal transition (EMT). PMID: 24305612 [PubMed - indexed for MEDLINE]
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Related Articles Erectile function restoration after repair of resected cavernous nerves by adipose-derived stem cells combined with autologous vein graft in rats. Cell Mol Neurobiol. 2014 Apr;34(3):393-402 Authors: Ying C, Hu W, Cheng B, Yang M, Zheng X, Wang X Abstract Cavernous nerve (CN) injury is the main cause of erectile dysfunction (ED) following radical prostatectomy. The recovery of erectile function following this procedure remains challenging. Here, we investigated the ability of adipose-derived stem cells (ADSCs) combined with autologous vein graft to improve erectile function in a rat model of bilateral long CN resection. Sprague-Dawley rats (n = 36) were randomized into four groups. Group A underwent sham operation. In Groups B, C, and D, an 8-mm segment of CN was excised bilaterally. In Group B and C, a 10-mm segment of autologous saphenous vein was interposed bilaterally at the site of injury, and the two nerve stumps were inserted into the vein lumen. 50 μL ADSCs were injected into each vein in Group B, and 50 μL of phosphate-buffered saline was injected in Group C. Group D underwent no repair. Erectile function assessed after 3 months by measuring intracavernosal pressure demonstrated significant recovery in erectile function in Group B with minimal recovery in Group C or D. Immunohistochemical staining showed that the nNOS-positive area was significantly larger in Group B than in Group D. ADSCs combined with autologous vein graft treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum. This procedure, therefore, provided a means of regenerating CN tissue and restoring autonomic erectile function after long bilateral CN resection (0.8 cm) in rats. PMID: 24398902 [PubMed - in process]
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Related Articles Xenogenic transplantation of human breast adipose-derived stromal vascular fraction enhances recovery of erectile function in diabetic mice. Biol Reprod. 2014 Mar;90(3):66 Authors: Das ND, Song KM, Yin GN, Batbold D, Kwon MH, Kwon KD, Kim WJ, Kim YS, Ryu JK, Suh JK Abstract The adipose tissue-derived stromal vascular fraction (SVF) is an ideal source of stem and stromal cells. The aim of this study was to examine whether and how xenogenic transplantation of human breast SVF restores erectile function in diabetic mice. Human SVF was isolated from five patients (age, 20-45 yr) undergoing reduction mammoplasty. Eight-week-old C57BL/6J mice were used, and diabetes was induced by intraperitoneal injection of streptozotocin. At 8 wk after induction of diabetes, the animals were randomly distributed into controls and diabetic mice treated with a single intracavernous injection of PBS, human SVF at different concentrations, or human SVF lysate. Two weeks later, erectile function was measured by cavernous nerve stimulation, and the penis was then harvested for biochemical examinations. Erectile function was significantly improved in diabetic mice treated with human SVF (2 × 10(5), 5 × 10(5), and 1 × 10(6) cells/20 μl) and SVF lysate. Human SVF treatment in diabetic mice significantly increased cavernous endothelial and smooth muscle cell contents, induced eNOS phosphorylation, and restored penile nNOS-positive nerve fibers. Human SVF lysate induced secretion of angiogenic factors and expression of their receptors. Human SVF did not increase serum levels of proinflammatory cytokines. A limitation of this study was that the exact composition of the human SVF was not examined. In summary, xenogenic transplantation of human SVF did not induce systemic inflammation and successfully improved erectile function in diabetic mice through enhanced penile angiogenesis and neural regeneration. PMID: 24501171 [PubMed - indexed for MEDLINE]
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Related Articles Adipose tissue-derived stem cell therapy for prevention and treatment of erectile dysfunction in a rat model of Peyronie's disease. Andrology. 2014 Mar;2(2):244-51 Authors: Gokce A, Abd Elmageed ZY, Lasker GF, Bouljihad M, Kim H, Trost LW, Kadowitz PJ, Abdel-Mageed AB, Sikka SC, Hellstrom WJ Abstract Peyronie's disease (PD) is a localized connective tissue disorder that involves the tunica albuginea (TA) of the penis. While surgical correction remains the gold standard, the search for an effective and less invasive therapy continues. The objective of this study was to evaluate the effects of intratunical injection of adipose tissue-derived stem cells (ADSCs) for the prevention and treatment of erectile dysfunction in a rat model of PD. Twenty-four male Sprague-Dawley rats (300-350 g) were randomly divided into four groups: sham, PD, PD + ADSC (prevention) and PD + ADSC (treatment). All rats underwent penile injections into the TA with 50 μL vehicle (sham) or 0.5 μg transforming growth factor (TGF)-β1 (remaining groups). The ADSC groups received intratunical injections with 0.5 million rat-labelled ADSCs on day 0 (prevention) or day 30 (treatment). Forty-five days following TGF-β1 injection, rats underwent cavernous nerve stimulation (CNS) with total intracavernous-to-mean arterial pressure ratio (ICP/MAP) and total ICP recorded to measure response to therapy. Tissues were evaluated histologically and for mRNA expression of tissue inhibitors of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs) and zymographic activity of MMPs. Statistical analysis was performed by analysis of variance followed by the Tukey test for post hoc comparisons. In both prevention and treatment groups, intratunical injection of ADSCs resulted in significantly higher ICP/MAP and total ICP in response to CNS compared with the PD group. Local injection of ADSCs prevented and/or reduced Peyronie's-like changes by decreasing the expression of TIMPs, and stimulating expression and activity of MMPs. This study documents the preventive and therapeutic benefits of ADSC on penile fibrosis and erectile function in an animal model of PD. PMID: 24574095 [PubMed - in process]
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Related Articles Rat cavernous nerve reconstruction with CD133+ cells derived from human bone marrow. J Sex Med. 2014 May;11(5):1148-58 Authors: Miyamoto K, Inoue S, Kobayashi K, Kajiwara M, Teishima J, Matsubara A Abstract INTRODUCTION: Erectile dysfunction remains a major complication after surgery of pelvic organs, especially after radical prostatectomy. AIM: The aim of this study was to assess the effect of endothelial progenitor cells on the regeneration of cavernous nerves in a rat injury model. METHODS: A 2 mm length of the right and left cavernous nerves of 8-week-old male nude rats were excised. Alginate gel sponge sheets supplemented with 1 × 10(4) CD133+ cells derived from human bone marrow were then placed over the gaps on both sides (CD group). The same experiments were performed on sham-operated rats (SH group), rats with only the nerve excision (EX group), and rats with alginate gel sheets placed on the injured nerves (AL group). MAIN OUTCOME MEASURES: Immunofluorescence staining and molecular evaluation were performed 4 days later. Functional and histological evaluations were performed 12 weeks later. RESULTS: The intracavernous pressure elicited by electrical stimulation and the neuronal nitric oxide synthase-positive area in surrounding tissues of the prostate was significantly greater in the CD group. Immunofluorescence microscopy showed that CD133+ cells were assimilated as vascular endothelial cells, and the real-time polymerase chain reaction showed upregulation of nerve growth factor and vascular endothelial growth factor in the alginate gel sponge sheets of the CD group. CONCLUSIONS: Transplantation of CD133+ cells accelerated the functional and histological recovery in this cavernous nerve injury model, and the recovery mechanism is thought to be angiogenesis and upregulation of growth factors. CD133+ cells could be an optional treatment for cavernous nerve injury after prostatectomy in clinical settings. PMID: 24576198 [PubMed - indexed for MEDLINE]
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Related Articles Long-term results of total body irradiation in adults with acute lymphoblastic leukemia. Strahlenther Onkol. 2014 May;190(5):453-8 Authors: Marnitz S, Zich A, Martus P, Budach V, Jahn U, Neumann O, Arnold R Abstract PURPOSE: The aim of this chart review of adult patients treated for acute lymphoblastic leukemia (ALL) with total body irradiation (TBI) was to evaluate early and late toxicity and long-term outcome. PATIENTS AND METHODS: A total of 110 adult patients (34 ± 12 years) with ALL underwent TBI (6 fractions of  2 Gy for a total of 12 Gy) as a part of the treatment regimen before transplantation. Treatment-related toxicity, mortality, and hematologic outcome are reported. RESULTS: Mean follow-up was 70 months. The 2- and 5-year leukemia-free survival rates were 78 and 72%, respectively. In all, 29% (32/110) patients suffered from medullary recurrence after a median time of 7 months. Gender was the only statistically significant prognostic factor in terms of overall survival in favor of female patients. Treatment-related mortality and overall survival after 2 and 5 years were 16 and 22%, and 60 and 52.7%, respectively. The most frequent late reaction wascGVHD of the skin (n = 33, 30%). In addition, 15.5% (17/110 patients) suffered pulmonary symptoms, and 6 patients developed lung fibrosis. Eyes were frequently affected by the radiation (31/110 = 28%); 12 of 110 patients (11%) presented with symptoms from osteoporosis, 5 of 110 patients (4.5%) developed hypothyreosis and 2 patients diabetes mellitus. Of the male patients, 11% reported erectile dysfunction or loss of libido, while 2 of 36 women reported menopausal syndrome at the mean time of 28 months after treatment with requirement for substitution. No women became pregnant after treatment. No acute or late cardiac toxicities were documented in our patients. No secondary malignancies were documented. CONCLUSION: Although hematologic outcome was in the upper range of that reported in the literature, treatment-related mortality (TRM) and medullary recurrences remain a challenge. Sophisticated radiation techniques allow for decreasing toxicity to certain organs and/or dose escalation to the bone marrow in highly selected patients in order to improve therapeutic breadth. PMID: 24595415 [PubMed - indexed for MEDLINE]
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Related Articles Human urine-derived stem cells alone or genetically-modified with FGF2 Improve type 2 diabetic erectile dysfunction in a rat model. PLoS One. 2014;9(3):e92825 Authors: Ouyang B, Sun X, Han D, Chen S, Yao B, Gao Y, Bian J, Huang Y, Zhang Y, Wan Z, Yang B, Xiao H, Songyang Z, Liu G, Zhang Y, Deng C Abstract AIM: The aim of this study was to determine the possibility of improving erectile dysfunction using cell therapy with either human urine-derived stem cells (USCs) or USCs genetically-modified with FGF2 in a type 2 diabetic rat model. METHODS: Human USCs were collected from 3 healthy donors. USCs were transfected with FGF2 (USCs-FGF2). Sixty-five SD male rats were divided into five groups (G). A control group of normal rats (G1, n = 10), and four other test groups of type 2 diabetic erectile dysfunction rats: PBS as a negative control (G2, n = 10), USCs (G3, n = 15), lentivirus-FGF2 (G4, n = 15), and USCs-FGF2 (G5, n = 15). Diabetes was induced in the rats via a high fat diet for 28 days and a subsequent intraperitoneal injection of streptozotocin (35 mg/kg). Erectile dysfunction was screened with apomorphine (100 μg/kg). Cell injections in the test groups (G2-G5) occurred directly into the corpora cavernosa. The implanted cells were tracked at 7 days (n = 5 animals/G) and 28 days (n = 10 animals/G) post injection. Mean arterial pressure (MAP), intracavernosal pressure (ICP), expression of endothelial markers (CD31, VEGF and eNOS), smooth muscle markers (desmin and smoothelin), histological changes and erectile function were assessed for each group. RESULTS: USCs expressed mesenchymal stem cell markers, and secreted a number of proangiogenic growth factors. USCs expressed endothelial cell markers (CD31 and vWF) after transfection with FGF2. Implanted USCs or USCs-FGF2 displayed a significantly raised ICP and ICP/MAP ratio (p<0.01) 28 days after intracavernous injection. Although few cell were detected within the implanted sites, histological and western blot analysis demonstrated an increased expression of endothelial and smooth muscle markers within the cavernous tissue following USC or USC-FGF2 injection. CONCLUSIONS: The paracrine effect of USCs or USCs-FGF2 induced improvement of erectile function in type 2 diabetic rats by recruiting resident cells and increasing the endothelial expression and contents of smooth muscle. PMID: 24663037 [PubMed - in process]
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Related Articles Combined effects of brain-derived neurotrophic factor immobilized poly-lactic-co-glycolic acid membrane with human adipose-derived stem cells and basic fibroblast growth factor hydrogel on recovery of erectile dysfunction. Tissue Eng Part A. 2014 Sep;20(17-18):2446-54 Authors: Lee SH, Kim IG, Jung AR, Shrestha KR, Lee JH, Park KD, Chung BH, Kim SW, Kim KH, Lee JY Abstract Erectile dysfunction (ED) is the most frequent long-term problem after radical prostatectomy. We aimed to evaluate whether the use of combination therapy with basic fibroblast growth factor (bFGF)-hydrogel on corpus cavernosum and with adipose-derived stem cells (ADSCs) and brain-derived neurotrophic factor (BDNF)-immobilized poly-lactic-co-glycolic acid (PLGA) membrane on the cavernous nerve (CN) could improve erectile function in a rat model of bilateral cavernous nerve crush injury (BCNI). Rats were randomly divided into five groups (n=15 per group): a normal group (N group), a group receiving saline application after bilateral cavernous nerve crush injury (BCNI), a group undergoing bFGF-hydrogel injection in the corpus cavernosum after BCNI (bFGF), a group receiving ADSC application covered with BDNF-membrane after BCNI (ADSC/BDNF), and a group undergoing coadministration of bFGF-hydrogel injection and BDNF-membrane with ADSCs after BDNF (bFGF+ADSC/BDNF). Four weeks postoperatively, the erectile function was assessed by detecting the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP). Smooth muscle and collagen contents were measured using Masson's trichrome staining. Neuronal nitric oxide synthase (nNOS) expression in the dorsal penile nerve was detected by immunostaining. The protein expression of the α-smooth muscle actin (α-SMA) and the cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum were quantified by western blot and cGMP assay, respectively. In the bFGF+ADSC/BDNF group, the erectile function was significantly elevated compared with the BCNI and other treated groups and showed a significantly increased smooth muscle/collagen ratio, nNOS content, α-SMA expression, and cGMP level. In particular, there were no statistical differences in the ICP/MAP ratio, smooth muscle/collagen ratio, and α-SMA and cGMP levels between the bFGF+ADSC/BDNF group and normal group. Application of the BDNF-immobilized PLGA membrane with human ADSC into the CN and bFGF-incorporated hydrogel into the corpus carvernosum improved nearly normal erectile function in a rat model of postprostatectomy ED. This result suggests that a combined application of bFGF+ADSC/BDNF might be a promising treatment for postprostatectomy ED. PMID: 24673637 [PubMed - in process]
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Related Articles Treatment of bladder dysfunction using stem cell or tissue engineering technique. Korean J Urol. 2014 Apr;55(4):228-38 Authors: Kim JH, Lee HJ, Song YS Abstract Tissue engineering and stem cell transplantation are two important options that may help overcome limitations in the current treatment strategy for bladder dysfunction. Stem cell therapy holds great promise for treating pathophysiology, as well as for urological tissue engineering and regeneration. To date, stem cell therapy in urology has mainly focused on oncology and erectile dysfunction. The therapeutic potency of stem cells (SCs) was originally thought to derive from their ability to differentiate into various cell types including smooth muscle. The main mechanisms of SCs in reconstituting or restoring bladder function are migration, differentiation, and paracrine effects. Nowadays, paracrine effects of stem cells are thought to be more prominent because of their stimulating effects on stem cells and adjacent cells. Studies of stem cell therapy for bladder dysfunction have been limited to experimental models and have been less focused on tissue engineering for bladder regeneration. Bladder outlet obstruction is a representative model. Adipose-derived stem cells, bone marrow stem cells (BMSCs), and skeletal muscle-derived stem cells or muscle precursor cells are used for transplantation to treat bladder dysfunction. The aim of this study is to review stem cell therapy and updated tissue regeneration as treatments for bladder dysfunction and to provide the current status of stem cell therapy and tissue engineering for bladder dysfunction including its mechanisms and limitations. PMID: 24741410 [PubMed]
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Related Articles Intracavernous delivery of stromal vascular fraction restores erectile function through production of angiogenic factors in a mouse model of cavernous nerve injury. J Sex Med. 2014 Aug;11(8):1962-73 Authors: Song KM, Jin HR, Park JM, Choi MJ, Kwon MH, Kwon KD, Batbold D, Yin GN, Kim WJ, Koh GY, Ryu JK, Suh JK Abstract INTRODUCTION: Erectile dysfunction (ED) is a major complication of radical prostatectomy. Men with radical prostatectomy-induced ED respond less positively to oral phosphodiesterase-5 inhibitors. AIM: The study aims to examine whether and how stromal vascular fraction (SVF) restores erectile function in mice with cavernous nerve injury (CNI). METHODS: Twelve-week-old male C57BL/6J mice were used and the animals were distributed into five groups: sham operation group and CNI group receiving a single intracavernous injection of phosphate-buffered saline (PBS) or SVF (1 × 10(4) , 1 × 10(5) , or 3 × 10(5) cells/20 μL, respectively). SVF was isolated from epididymal adipose tissues of green fluorescence protein transgenic mice. MAIN OUTCOME MEASURES: Two weeks after injection, erectile function was measured by cavernous nerve stimulation. The penis was stained with antibodies to platelet/endothelial cell adhesion molecule-1, phosphohistone H3, and phosphorylated endothelial nitric oxide synthase (phospho-eNOS). We also performed Western blot for angiopoietin-1 (Ang-1), vascular endothelial growth factor-A, hepatocyte growth factor, phospho-eNOS, and eNOS in the corpus cavernosum tissue. RESULTS: Local delivery of SVF restored erectile function in a dose-dependent manner in CNI mice. The highest erectile response was noted at a dose of 3 × 10(5) cells, for which the response was comparable with that in the sham operation group. Local delivery of SVF significantly increased the expression of angiogenic factor proteins and induced cavernous endothelial cell proliferation and eNOS phosphorylation compared with that in the PBS-treated CNI group. SVF-induced promotion of cavernous angiogenesis and erectile function was diminished in the presence of soluble antibody to Tie2, a receptor tyrosine kinase of Ang-1. CONCLUSION: Secretion of angiogenic factors from SVF is an important mechanism by which SVF induces cavernous endothelial regeneration and restores erectile function. These findings suggest that cavernous endothelial regeneration by using SVF may represent a promising treatment strategy for radical prostatectomy-induced ED. PMID: 24902866 [PubMed - indexed for MEDLINE]
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Related Articles In vivo determination of muscle-derived stem cells in the rat corpus cavernosum. Exp Ther Med. 2014 Jul;8(1):274-280 Authors: Xu L, Xue B, Shan Y, Chen D, Gao J, Yang D, Sun C, Cui Y Abstract The aim of the present in vivo study was to determine the presence of muscle-derived stem cells (MDSCs) in the corpus cavernosum of rats. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were performed to detect the expression of the stem cell markers stem cell antigen-1 (Sca-1), Oct4 and Desmin in Sprague-Dawley rats aged 2, 5 and 20 months. Sca-1 was mainly expressed in the blood vessels and cavernous sinus and staining revealed that Sca-1 was predominantly expressed in the cytoplasm. Desmin was primarily expressed in muscular tissues and staining demonstrated that it was mainly expressed in the cytoplasm, however, Desmin was also partially expressed in the nuclei. A small number of double positive cells, expressing Sca-1 and Desmin, were also detected near the cavernous sinus. It was found that the expression of the markers was negatively correlated with the age of the rats (P<0.05). The results from the RT-PCR demonstrated that the expression levels of Sca-1 and Desmin significantly decreased with age (P<0.05). In addition, the correlation analysis indicated that the expression of Sca-1 and Desmin were negatively correlated with the age of the rats (r=--0.929; P<0.05). In conclusion, the present study provided evidence for the presence of MDSCs in the rat corpus cavernosum. MDSCs may be a potential therapeutic treatment for organic erectile dysfunction. PMID: 24944634 [PubMed - as supplied by publisher]
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Related Articles Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse. Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):E2731-40 Authors: Yin GN, Choi MJ, Kim WJ, Kwon MH, Song KM, Park JM, Das ND, Kwon KD, Batbold D, Oh GT, Koh GY, Kim KW, Ryu JK, Suh JK Abstract Penile erection is a neurovascular phenomenon, and erectile dysfunction (ED) is caused mainly by vascular risk factors or diseases, neurologic abnormalities, and hormonal disturbances. Men with diabetic ED often have severe endothelial dysfunction and peripheral nerve damage, which result in poor response to oral phosphodiesterase-5 inhibitors. Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period. Here, we demonstrate in streptozotocin-induced diabetic mice that inhibition of the Ninj1 pathway by administering Ninj1-neutralizing antibody (Ninj1-Ab) or by using Ninj1-knockout mice successfully restored erectile function through enhanced penile angiogenesis and neural regeneration. Angiopoietin-1 (Ang1) expression was down-regulated and angiopoietin-2 expression was up-regulated in the diabetic penis compared with that in controls, and these changes were reversed by treatment with Ninj1-Ab. Ninj1 blockade-mediated penile angiogenesis and neural regeneration as well as recovery of erectile function were abolished by inhibition of Ang1-Tie2 (tyrosine kinase with Ig and epidermal growth factor homology domain-2) signaling with soluble Tie2 antibody or Ang1 siRNA. The present results suggest that inhibition of the Ninj1 pathway will be a novel therapeutic strategy for treating ED. PMID: 24979788 [PubMed - indexed for MEDLINE]
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Related Articles Therapeutic potential of adipose-derived stem cells-based micro-tissues in a rat model of postprostatectomy erectile dysfunction. J Sex Med. 2014 Oct;11(10):2439-48 Authors: Xu Y, Guan R, Lei H, Li H, Wang L, Gao Z, Song W, Xin Z Abstract INTRODUCTION: Stem cells (SCs) show significant benefits in the treatment of postprostatectomy erectile dysfunction (ED). However, the low retention rate of the traditional single-cell strategy at the injection sites limits its therapeutic potential. AIM: This study aims to investigate the feasibility and mechanism of adipose-derived stem cells (ADSCs)-based micro-tissues (MTs) in the treatment of ED in a rat model of bilateral cavernous nerves (CNs) injury. METHODS: ADSCs labeled with 5-ethynyl-2-deoxyuridine (EdU) were used to generate MTs with hanging drop method. 10 Sprague-Dawley (SD) rats underwent sham surgery and intracavernous (IC) injection of phosphate buffer solution (PBS) (the sham group). Another 70 rats underwent bilateral CN crush and were then treated with PBS (n = 10, the crush group), dissociated ADSCs (n = 30, the ADSCs group), and MTs (n = 30, the MTs group), respectively. At day 1, 3, 7, 14 (n = 5), and 28 (n = 10) postsurgery, specimens were harvested for histology. At day 28, 10 rats in each group were examined for erectile function before tissue harvest. MAIN OUTCOME MEASURES: Light microscopy of the dynamic aggregation of the MT, immunohistologic examination of the MTs, the retention and distribution of EdU + ADSCs in the corpus cavernosum (CC), and the penis histological analyses of collagen content, Western blot of functional proteins in MTs, intracavernous pressure recording on CN electrostimulation. RESULTS: Three-day-old MTs became stable and expressed nerve growth factor, vascular endothelial growth factor, C-X-C chemokine receptor type 4, Wnt5a, and collagen IV. More EdU + ADSCs retained in the CC in the MTs group than that in the ADSCs group. IC injection of MTs resulted in significant restoration of the erectile function and histopathological changes compared with the ADSCs group. CONCLUSION: IC-injected MTs resulted in a better restoration of erectile function than traditional single-cell strategy. The underlying mechanisms of recovery appear to involve enhanced cellular retention in the penis and upregulation of some paracrine factors. Xu Y, Guan R, Lei H, Li H, Wang L, Gao Z, Song W, and Xin Z. Therapeutic potential of adipose-derived stem cells-based micro-tissues in a rat model of postprostatectomy erectile dysfunction. J Sex Med 2014;11:2439-2448. PMID: 25042722 [PubMed - in process]
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Related Articles Mesenchymal stem cell therapy in treatment of erectile dysfunction: Autologous or allogeneic cell sources? Int J Urol. 2014 Jul 30; Authors: Mangir N, Akbal C, Tarcan T, Simsek F, Turkeri L Abstract OBJECTIVE: To compare the efficacy of intracavernosal injection of autologous and allogeneic mesenchymal stem cells as potential treatment of erectile dysfunction in an experimental rat model. METHODS: Mesenchymal stem cells were isolated from rat paratesticular fat tissue. Bilateral cavernous nerve injury was carried out followed by immediate intracavernosal injection of either autologous or allogeneic mesenchymal stem cells or mesenchymal stem cell lysates. One month after injection, erectile function was evaluated by means of intracavernosal pressure measurement. All rats were eventually killed, and penile tissues were taken for immunhistochemical and molecular investigation. RESULTS: A total of 36 Sprague-Dawley rats were used. The mean maximum intracavernosal pressure in the sham-operated, autologous and allogeneic mesenchymal stem cell injection groups were significantly better compared with the vehicle injection group (80.5 [3.56], 71.1 [2.9] and 69.2 [3.2] vs 40.33 [4.4], respectively). Mean maximum intracavernosal pressure to mean arterial pressure ratios in the autologous and allogeneic mesenchymal stem cell and mesenchymal stem cell lysate injection groups were not significantly different. CONCLUSIONS: Intracavernosal injection of both autologous or allogeneic mesenchymal stem cells improve erectile functions in a rat model of cavernous nerve injury. Allogeneic mesenchymal stem cells might provide clinicians with ready to use, standardized and, in certain cases, more effective products. More studies focusing on long-term immunological aspects of allogeneic mesenchymal stem cells are required. PMID: 25074479 [PubMed - as supplied by publisher]
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Related Articles 2014 Update Of Erectile Dysfunction Management Following Radical Prostatectomy: From Basic Research To Clinical Management. Curr Pharm Des. 2014 Oct 29; Authors: Gur S, Sikka SC, Kadowitz PJ, Silberstein J, Hellstrom WJ Abstract Radical prostatectomy (RP) is the most commonly employed curative intervention for the treatment of prostate cancer. However, due to the proximity of the cavernous nerves (CN) to the prostate, RP results in transient and/often permanent erectile dysfunction (ED). While the prevention of traction injuries during the RP is critical for the preservation of erectile function, several preclinical studies have demonstrated the beneficial effects of neuroprotective (or neuroregenerative) agents in mitigating neuronal injuries sustained during RP. The maintenance or restoration of erectile function after injury may be enhanced in the postoperative period by the stimulation of neurogenesis to protect and restore injured nerves from further deterioration. The present review aims to evaluate and summarize research of these treatment strategies as published in the National Library of Medicine (Pubmed) from 2000 to 2014. The keywords used for the search were ED, RP, CN injury, immunophilin ligands, neurotrophins and phosphodiesterase (PDE)-5 inhibitors, and animal models. Current guidelines for treatment targeting CN recovery recommend the use of immunophilin ligands, neurotrophins, brain-derived neurotrophic factor, glial cell-line derived neurotrophic factor, sonic hedgehog (Shh), Rho-kinase, PDE-5 inhibitors, erythropoietin (EPO), hyperbaric oxygen therapy, super enzyme gene therapy, stem cells, and triiodothyronine (T3) therapy. Additionally, this review identifies remaining gaps in general knowledge and recent updates recognizing the need for further preclinical and clinical trials. PMID: 25354178 [PubMed - as supplied by publisher]
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Related Articles Implications for Differentiation of Endogenous Stem Cells: Therapeutic Effect from Icariside II on a Rat Model of Postprostatectomy Erectile Dysfunction. Stem Cells Dev. 2014 Nov 3; Authors: Xu Y, Guan R, Lei H, Gao Z, Li H, Hui Y, Zhou F, Wang L, Lin G, Xin Z Abstract Self-renewal and differentiation of endogenous stem cells (SCs) are essential for adult tissue homoeostasis and intrinsic healing capacity. In this study, we hypothesize that penis contains a small population of endogenous SCs, which might help rejuvenation of damaged erectile function. In this study, 60 newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous SCs. Twelve weeks later, 48 rats underwent bilateral cavernous nerves injury and were randomized into gavage feeding of solvent (vehicle group) or icariside II (0.5, 1.5, and 4.5 mg/kg/day, respectively). Twelve sham-operated rats received vehicle treatment and served as control. The treatments were continued for 4 weeks followed by a washout period of 72 h. Results showed that ICA II treatment significantly restored erectile function and effectively prevented distortion of normal neural anatomy, smooth muscle atrophy, and collagen deposition compared with the vehicle group. The numbers of label-retaining cells (LRCs) coexpressing EdU and differentiated phenotypes (smooth muscle marker α-SMA or Schwann cell marker S100) were significantly higher in the three ICA II-treated groups than those in vehicle group in a dose-dependent manner. In addition, the changing trend of p38 mitogen-activated protein kinase (MAPK) activity in the penis between groups was same as that of the number of differentiated LRCs. Together, these results suggest that the underlying mechanisms of ICA II in ameliorating erectile function and pathological changes appear to involve enhanced endogenous SCs differentiation, which might be regulated by p38 MAPK signaling pathway. PMID: 25365340 [PubMed - as supplied by publisher]
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