Stem Cell Treatment for Degenerative Disc Disease

Stem Cell Treatment for Degenerative Disc Disease

Degeneration of the intervertebral disc, often called "degenerative disc disease" (DDD) of the spine, is a condition that can be painful and can greatly affect the quality of one's life.

STEM CELL TREATMENT DEGENERATIVE DISC DISEASE

While disc degeneration is a normal part of aging and for most people is not a problem, for certain individuals a degenerated disc can cause severe constant chronic pain. Often, degenerative disc disease can be successfully treated without surgery. One or a combination of treatments such as physical therapy, chiropractic manipulative therapy (CMT) and other chiropractic treatments, osteopathic manipulation, anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs, traction, or spinal injections often provide adequate relief of these troubling symptoms.

Degenerative discs typically show degenerative fibrocartilage and clusters of chondrocytes, suggestive of repair. Inflammation may or may not be present. Histologic examination of disc fragments resected for presumed DDD is routine to exclude malignancy.

Fibrocartilage replaces the gelatinous mucoid material of the nucleus pulposus as the disc changes with age. There may be splits in the annulus fibrosis, permitting herniation of elements of nucleus pulposus. There may also be shrinkage of the nucleus pulposus that produces prolapse of the annulus with secondary osteophyte formation at the margins of the adjacent vertebral body.

The pathologic findings in DDD include protrusion, spondylolysis, and/or subluxation of vertebrae (sponylolisthesis) and spinal stenosis.

STEM CELL TREATMENT FOR DEGENERATIVE DISC DISEASE

Stem Cell Treatment and Degenerative Disc Disease NIH Streaming Database

Related Articles Maintaining and restoring mobility in middle and old age: the importance of the soft tissues. Instr Course Lect. 1997;46:459-69 Authors: Buckwalter JA Abstract For many older individuals, impairment of musculoskeletal function, especially weakness, stiffness, and pain, cause progressive disability, thereby limiting mobility and decreasing the quality of life. With advancing age, musculoskeletal soft tissue function declines, susceptibility to degenerative diseases and injuries increases, and the ability to recover from disease or injury declines; these changes increase the probability of impairment (Fig. 1). However, the function of individual cells, tissues, or organ systems may remain stable or even improve temporarily with age, and a number of interventions have the potential to maintain or improve musculoskeletal function. Age-related changes in cells, tissues, and musculoskeletal function are not necessarily unidirectional or uniform among individuals, organ systems, tissues, or cells, nor are they necessarily irreversible. Surgical procedures can restore mobility for many patients with age-related musculoskeletal injuries or degenerative diseases. Regular resistance and range-of-motion exercises can decrease the age-related loss of strength and help maintain or restore flexibility. However, exercise programs can also cause injury. Older individuals should have a careful medical evaluation before starting an exercise program, and the program should be selected based on this evaluation. This is especially important for individuals with systemic illness and for individuals at greater risk of musculoskeletal injury, including people with previous joint injuries, obesity, osteoarthritis, joint deformity, weakness, or restricted joint motion. Trophic hormone replacement or supplementation may also modify age-related changes in the soft tissues, including loss of strength, but these hormones have adverse effects. Systemic or local use of growth factors and cell transplantation after expanding the population of mesenchymal stem cells in culture could improve healing in older people. Other potential methods of slowing or reversing age-related deterioration of the soft tissues include inhibition of posttranslational modification of matrix proteins and alteration of the activity of selected transcription factors. In particular, better understanding of the role of transcription factors in cell sequence may make it possible to devise methods of delaying or reversing age-related loss of cell proliferative and synthetic capacity. PMID: 9143988 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials. 2003 Sep;24(20):3531-41 Authors: Sakai D, Mochida J, Yamamoto Y, Nomura T, Okuma M, Nishimura K, Nakai T, Ando K, Hotta T Abstract Intervertebral disc degeneration is considered to be one of the major causes of low back pain. Despite this irreversible phenomenon, attempts to decelerate disc degeneration using various techniques have been reported. However, to date there has been no proven technique effective for broad clinical application. Based on previous studies, we hypothesize that maintenance of proteoglycan content in the disc is achieved by avoiding the depletion of nucleus pulposus and preserving the structure of the annulus is a primary factor in decelerating disc degeneration. One novel approach to solve the dilemma of intervertebral disc degeneration is found at the stem cell level. Mesenchymal stem cells (MSCs) are known to possess the ability to differentiate into various kinds of cells from mesenchymal origin. Although the majority of cells that contribute to disc formation are known to obtain chondrocyte-like phenotypes, no reported study has emphasized the correlation with mesenchymal stem cells. To evaluate the possible potential of MSCs in disc cell research and treatment of degenerative disc disease, autologous MSCs embedded in Atelocollagen gel were transplanted into the discs of rabbits which had undergone a procedure proven to induce degeneration. The results suggest that MSC transplantation is effective in decelerating disc degeneration in experimental models and provided new hopes for treatment of degenerative disc disease in humans. Atelocollagen gel served as an important carrier of MSCs in transplantation, permitting proliferation, matrix synthesis and differentiation of MSCs. This study strengthens the viable efficacy of practical application of MSCs in treatment of intervertebral disc disease. PMID: 12809782 [PubMed - indexed for MEDLINE]
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Related Articles Light-activated gene transduction of recombinant adeno-associated virus in human mesenchymal stem cells. Gene Ther. 2004 Jan;11(1):34-41 Authors: Ito H, Goater JJ, Tiyapatanaputi P, Rubery PT, O'Keefe RJ, Schwarz EM Abstract Deficiencies in skeletal tissue repair and regeneration lead to conditions like osteoarthritis, osteoporosis and degenerative disc disease. While no cure for these conditions is available, the use of human bone marrow derived-mesenchymal stem cells (HuMSCs) has been shown to have potential for cell-based therapy. Furthermore, recombinant adeno-associated viruses (rAAV) could be used together with HuMSCs for in vivo or ex vivo gene therapy. Unfortunately, the poor transduction efficiency of these cells remains a significant obstacle. Here, we describe the properties of ultraviolet (UV) light-activated gene transduction (LAGT) with rAAV in HuMSCs, an advance toward overcoming this limitation. Using direct fluorescent image analysis and real-time quantitative PCR to evaluate enhanced green fluorescent protein (eGFP) gene expression, we found that the optimal effects of LAGT with limited cytotoxicity occurred at a UV dose of 200 J/m(2). Furthermore, this UV irradiation had no effect on either the chondrogenic or osteogenic potential of HuMSCs. Significant effects of LAGT in HuMSCs could be detected as early as 12 h after exposure and persisted over 21 days, in a time and energy-dependent manner. This LAGT effect was maintained for more than 8 h after irradiation and required only a 10-min exposure to rAAV after UV irradiation. Finally, we show that the production of secreted TGFbeta1 protein from rAAV-TGFbeta1-IRES-eGFP infected to HuMSCs is highly inducible by UV irradiation. These results demonstrate that LAGT combined with rAAV is a promising procedure to facilitate gene induction in HuMSCs for human gene therapy. PMID: 14681695 [PubMed - indexed for MEDLINE]
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Related Articles Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy. Spine (Phila Pa 1976). 2004 Dec 1;29(23):2627-32 Authors: Risbud MV, Albert TJ, Guttapalli A, Vresilovic EJ, Hillibrand AS, Vaccaro AR, Shapiro IM Abstract OBJECTIVE: Because mesenchymal stem cells can differentiate into chondrocyte-like cells, we ask the question, can mesenchymal stem cells commit to the nucleus pulposus phenotype? BACKGROUND: Back pain, a significant source of morbidity in our society, is linked to degenerative changes of the intervertebral disc. Absence of suitable graft tissue limits therapeutic approaches for repair of disc tissue. For this reason, there is considerable interest in developing "tissue engineering" strategies for the regeneration of the nucleus pulposus. METHODS: Rat mesenchymal stem cells were immobilized in 3-dimensional alginate hydrogels and cultured in a medium containing transforming growth factor-beta1 under hypoxia (2% O2) and normoxia (20% O2). Mesenchymal stem cells were examined by confocal microscopy to evaluate their viability and metabolic status after labeling with Celltracker green, a thiol sensitive dye, and Mitotracker red, a dye sensitive to the mitochondrial membrane potential. Flow cytometry, semiquantitative reverse transcription polymerase chain reaction and Western blot analysis were carried out to evaluate phenotypic and biosynthetic activities and the signaling pathways involved in the differentiation process. RESULTS: Under hypoxic conditions, mesenchymal stem cells formed large aggregates and exhibited positive Celltracker and Mitotracker signals. Glucose transporter-3, matrix metalloproteinase-2, collagen type II and type XI, and aggrecan mRNA and protein expression was upregulated, whereas there was no change in the levels of decorin, biglycan, fibromodulin, and lumican. Hypoxia maintained the expression of CD44 (hyaluronan receptor), ALCAM (CD166), and endoglin (transforming growth factor-beta receptor). Likewise, expression of beta3 and alpha2 integrin was upregulated. Transforming growth factor-beta treatment increased MAPK activity and Sox-9, aggrecan, and collagen type II gene expression. Basal levels of the phosphorylated MAPK isoform ERK1/2, but not p38, were higher under hypoxic conditions than normoxia, and its activation was further augmented by treatment of cells with transforming growth factor-beta. In hypoxia, transforming growth factor-beta sustained phosphorylated p38 expression for an extended time period. Pharmacological inhibition of ERK1/2 and p38 enzymatic activity resulted in a decrease in Sox-9, aggrecan, and collagen type II mRNA levels. CONCLUSIONS: Our results indicate that hypoxia and transforming growth factor-beta drive mesenchymal stem cell differentiation towards a phenotype consistent with that of the nucleus pulposus. Measurement of selected signaling molecules and response to specific inhibitors suggest involvement of MAPK signaling pathways. It is concluded that mesenchymal stem cells could be used to repopulate the damaged or degenerate intervertebral disc. PMID: 15564911 [PubMed - indexed for MEDLINE]
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Related Articles [Biological approach for treatment of degenerative disc diseases]. Clin Calcium. 2005 Mar;15(3):79-86 Authors: Nishida K, Doita M, Takada T, Shimomura T, Maeno K, Kakutani K, Miyamoto H, Kurosaka M Abstract Intervertebral disc degeneration and associated spinal disorders including low back pain are a leading source of morbidity and a major cause of work disability as well as increased health care costs. Recent advance of molecular biology enable us to utilize these new techniques for understanding disc cell function and mechanisms of disc degeneration. Furthermore, these new technology may open novel therapeutic strategy such as application of growth factors, stem cell therapy, and gene therapy to regenerate degenerated intervertebral discs. PMID: 15741683 [PubMed - indexed for MEDLINE]
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Related Articles Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. Biomaterials. 2006 Jan;27(3):335-45 Authors: Sakai D, Mochida J, Iwashina T, Hiyama A, Omi H, Imai M, Nakai T, Ando K, Hotta T Abstract Intervertebral disc (IVD) degeneration, a common cause of low back pain in humans, is a relentlessly progressive phenomenon with no currently available effective treatment. In an attempt to solve this dilemma, we transplanted autologous mesenchymal stem cells (MSCs) from bone marrow into a rabbit model of disc degeneration to determine if stem cells could repair degenerated IVDs. LacZ expressing MSCs were transplanted to rabbit L2-L3, L3-L4 and L4-L5 IVDs 2 weeks after induction of degeneration. Changes in disc height by plain radiograph, T2-weighted signal intensity in magnetic resonance imaging (MRI), histology, immunohistochemistry and matrix associated gene expressions were evaluated between normal controls (NC) without operations, sham operated with only disc degeneration being induced, and MSC-transplanted animals for a 24-week period. Results showed that after 24 weeks post-MSC transplantation, degenerated discs of MSC-transplanted group animals regained a disc height value of about 91%, MRI signal intensity of about 81%, compared to NC group discs. On the other hand, sham-operated group discs demonstrated the disc height value of about 67% and MRI signal intensity of about 60%. Macroscopic and histological evaluations confirmed relatively preserved nucleus with circular annulus structure in MSC-transplanted discs compared to indistinct structure seen in sham. Restoration of proteoglycan accumulation in MSC-transplanted discs was suggested from immunohistochemistry and gene expression analysis. These data indicate that transplantation of MSCs effectively led to regeneration of IVDs in a rabbit model of disc degeneration as suggested in our previous pilot study. MSCs may serve as a valuable resource in cell transplantation therapy for degenerative disc disease. PMID: 16112726 [PubMed - indexed for MEDLINE]
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Related Articles The potential role of mesenchymal stem cell therapy for intervertebral disc degeneration: a critical overview. Neurosurg Focus. 2005 Sep 15;19(3):E4 Authors: Acosta FL, Lotz J, Ames CP Abstract Low-back pain is the most common health problem for men and women between 20 and 50 years of age, resulting in 13 million doctor visits in the US annually, with significant costs to society in terms of lost time from work and direct and indirect medical expenses. Although the exact origin of most cases of low-back pain remains unknown, it is understood that degenerative damage to the intervertebral disc (IVD) plays a central role in the pathogenic mechanism leading to this disorder. Current treatment modalities for disc-related back pain (selective nerve root blocks, surgical discectomy and fusion) are costly procedures aimed only at alleviating symptoms. Consequently, there is growing interest in the development of novel technologies to repair or regenerate the degenerated IVD. Recently, mesenchymal stem cells (MSCs) have been found to possess the capacity to differentiate into nucleus pulposus-like cells capable of synthesizing a physiological, proteoglycan-rich extracellular matrix characteristic of healthy IVDs. In this article, the authors review the use of MSCs for repopulation of the degenerating IVD. Although important obstacles to the survival and proliferation of stem cells within the degenerating disc need to be overcome, the potential for MSC therapy to slow or reverse the degenerative process remains substantial. PMID: 16190603 [PubMed - indexed for MEDLINE]
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Related Articles Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model: potential and limitations for stem cell therapy in disc regeneration. Spine (Phila Pa 1976). 2005 Nov 1;30(21):2379-87 Authors: Sakai D, Mochida J, Iwashina T, Watanabe T, Nakai T, Ando K, Hotta T Abstract STUDY DESIGN: An in vivo study to assess the differentiation status of mesenchymal stem cells (MSCs) transplanted to the nucleus pulposus of degenerative discs in a rabbit model. OBJECTIVES: To evaluate the fate of MSCs transplanted to the nucleus pulposus of degenerative discs in a rabbit and to determine whether they are a suitable alternative for cell transplantation therapy for disc degeneration. SUMMARY OF BACKGROUND DATA: Although MSCs have been proposed as candidate donor cells for transplantation to treat intervertebral disc degeneration, their differentiation after transplantation has not been adequately investigated. METHODS: Autologous MSCs, labeled with green fluorescent protein, were transplanted into mature rabbits. Consecutive counts of transplanted MSCs in the nucleus area were performed for 48 weeks after transplantation. Differentiation of transplanted cells was determined by immunohistochemical analysis. The proteoglycan content of discs was measured quantitatively using a dimethylmethylene blue assay, and mRNA expression of Type I and II collagen, aggrecan and versican was measured semi-quantitatively using reverse transcription polymerase chain reaction. RESULTS: Many cells that were positive for green fluorescent protein were observed in the nucleus pulposus of cell-transplanted rabbit discs 2 weeks after transplantation. Their number increased significantly by 48 weeks. Some GFP-positive cells were positive for cell-associated matrix molecules, such as Type II collagen, keratan sulfate, chondroitin sulfate, aggrecan, and the nucleus pulposus phenotypic markers, hypoxia inducible factor 1 alpha, glutamine transporter 1, and matrix metalloproteinase 2. MSCs did not show significant expression of these molecules before transplantation. Biochemical and gene expression analyses showed significant restoration of total proteoglycan content and matrix-related genes compared with nontransplanted discs. CONCLUSIONS: MSCs transplanted to degenerative discs in rabbits proliferated and differentiated into cells expressing some of the major phenotypic characteristics of nucleus pulposus cells, suggesting that these MSCs may have undergone site-dependent differentiation. Further studies are needed to evaluate their functional role. PMID: 16261113 [PubMed - indexed for MEDLINE]
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Related Articles Cell-based therapy for disc repair. Spine J. 2005 Nov-Dec;5(6 Suppl):297S-303S Authors: Anderson DG, Risbud MV, Shapiro IM, Vaccaro AR, Albert TJ Abstract BACKGROUND CONTEXT: One of the most promising therapies for symptomatic disc degeneration involves the implantation of therapeutic cells into the degenerative disc. PURPOSE: In this article, the rationale and approaches for cell-based tissue engineering of the intervertebral disc are discussed. STUDY DESIGN: The scientific literature related to cell-based tissue engineering of the intervertebral disc is reviewed. METHODS: A variety of cell types have been used in various research models to affect matrix repair of the intervertebral disc. The use of cellular scaffolds and growth factors or genes also appears promising for achieving meaningful tissue repair of the intervertebral disc. RESULTS: Disc tissue engineering is a promising approach for achieving repair of the intervertebral disc. Using cell-based approaches, various research models suggest that improvements in the complex matrix of the disc may be achieved. CONCLUSION: A cell-based approach to repair of the intervertebral disc appears promising. More research is needed to define the optimal cell type, cellular scaffold and mixture of growth factors that may allow meaningful repair of the human symptomatic degenerative disc. PMID: 16291126 [PubMed - indexed for MEDLINE]
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Related Articles Stem cells in orthopedics: current concepts and possible future applications. Indian J Med Sci. 2006 Apr;60(4):162-9 Authors: Bagaria V, Patil N, Sapre V, Chadda A, Singrakia M Abstract Stem cells are the cells that have the ability to divide for indefinite periods in culture and to give rise to specialized cells. Sources of these cells include embryo, umbilical cord and certain sites in adults such as the central nervous system [CNS] and bone marrow. Its use hold promise of wide spread applications particularly in areas of spinal cord injury, difficult non-unions, critical bone defects, spinal fusions, augmentation of ligament reconstructions, cartilage repair and degenerative disc disorders. This review article contains current information derived from Medline searches on the use in various orthopedic subspecialties. Some issues remain at the forefront of the controversy involving stem cell research - legislation, ethics and public opinion, cost and concentration methods. As is true with any new technology, the enthusiasm for this technology that has potential to influence virtually every orthopedic case management, must be balanced by subjecting it to stringent clinical and basic research investigations. PMID: 16679634 [PubMed - indexed for MEDLINE]
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Related Articles Interaction of human mesenchymal stem cells with disc cells: changes in extracellular matrix biosynthesis. Spine (Phila Pa 1976). 2006 Aug 15;31(18):2036-42 Authors: Le Visage C, Kim SW, Tateno K, Sieber AN, Kostuik JP, Leong KW Abstract STUDY DESIGN: To evaluate the in vitro interactions between human mesenchymal stem cells (MSCs) and degenerative disc cells. OBJECTIVES: To demonstrate the potential of MSCs in regulating the extracellular matrix synthesis of degenerative disc cells. SUMMARY OF BACKGROUND DATA: Culture of degenerative disc cells followed by their reinsertion into a disc can retard the degeneration process in an animal model. However, harvesting cells without accelerating degeneration is problematic. Autologous MSCs can be safely harvested from the bone marrow and transplanted into degenerative discs. METHODS: Human degenerative nucleus pulposus (NP), anulus fibrosus (AF) cells, and MSCs were cultured as pellets, and coculture pellets were formed by addition of MSCs to disc cells (50:50 ratio). Glycosaminoglycan (GAG) and DNA content were measured. Proteoglycan synthesis was analyzed by RT-PCR and western blot. Type II collagen expression was assessed by immunohistochemistry. RESULTS: Coculture pellets formed by the addition of MSCs to AF cells were superior in size to all other pellets. AF/MSC pellets showed higher experimental GAG content than the predicted values represented by the sum of individual control pellets, with 10.2 versus 5.6 microg/pellet at week 3, respectively. The effect was not observed in the NP/MSC coculture, or when chondrogenic medium was used. Close contact between cells was necessary to obtain this enhancement of GAG content. Proteoglycan and collagen expression in both individual and coculture pellets was confirmed by PCR analysis and western blot. CONCLUSION: Addition of MSCs to AF cells resulted in an up-regulation of the proteoglycans synthesis. This study provides the rationale for further investigation of the potential of MSC therapy in treating intervertebral disc degeneration. PMID: 16915085 [PubMed - indexed for MEDLINE]
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Related Articles Adipose-derived stem cell therapy for intervertebral disc regeneration: an in vitro reconstructed tissue in alginate capsules. Tissue Eng Part A. 2008 Aug;14(8):1415-23 Authors: Gaetani P, Torre ML, Klinger M, Faustini M, Crovato F, Bucco M, Marazzi M, Chlapanidas T, Levi D, Tancioni F, Vigo D, Rodriguez y Baena R Abstract The degenerative pathologies of the intervertebral disc have a remarkable social impact in the industrialized countries and can provide serious disabilities in the population. The current treatment consists of conservative treatments (such as symptomatic pharmacological therapies and physiokinetic therapy) and surgical treatments (intervertebral fusion, total disc replacement, nucleus pulposus (NP) replacement, or surgical exeresis). Recent advances in cell therapy foresee the possibility of regenerating the damaged disc; the autologous disc tissue can be withdrawn, in vitro regenerated, and re-implanted. The aim of this work was to verify whether autologous adipose-derived adult stem cells can improve the quality of an in vitro reconstructed nucleus pulposus tissue. A three-dimensional (3D) co-culture of NP cells and adipose tissue non-adipocyte fraction cells (nAFs) was assessed in a previously developed alginate 3D culture system following the good manufacturing practice guidelines to ensure patient safety for clinical studies. Morphological investigation of cultured and co-cultured cells was performed using transmission electron microscopy and immunofluorescence for collagen type I, aggrecan, CD90, CD34, and vimentin. Results indicate that co-culture of NP and nAFs improves the quality of the in vitro reconstructed tissue in term of extracellular matrix production and 3D cell organization. Technological resources are available for NP cell encapsulation intended for regenerating the intervertebral disc. PMID: 18593270 [PubMed - indexed for MEDLINE]
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Related Articles The clinical use of enriched bone marrow stem cells combined with porous beta-tricalcium phosphate in posterior spinal fusion. Biomaterials. 2008 Oct;29(29):3973-82 Authors: Gan Y, Dai K, Zhang P, Tang T, Zhu Z, Lu J Abstract Cytotherapy for bone regeneration has not been widely used clinically. A new method based on enriched bone-marrow-derived mesenchymal stem cells (MSCs) combined with porous beta-tricalcium phosphate (beta-TCP) was used for posterior spinal fusion in 41 patients. The aim of the present study was to assess the clinical feasibility of peri-operative bone marrow stem cell enrichment and their combination with tricalcium phosphate. About 252 ml marrow per patient was harvested from bilateral iliac crest, the enriched MSCs were produced by a cell processor peri-operatively, then combined with porous beta-TCP granules by a negative pressure and a short-time incubation in the meantime of conventional operation, which were finally implanted back into the patient. About 45 ml enriched MSC suspension was collected, and 78+/-16% of MSCs were recovered. By enrichment technique, the number of colony-forming units which expressed alkaline phosphatase (CFUs-ALP+, to estimate the prevalence of MSCs) was increased 4.3 times; the increasing folds of bone marrow nucleated cells (NCs) and MSCs had a positive correlation. The natural log (ln) of MSC number declined with age, and also, the MSC number of younger subjects (< or =40 years) was more than that of older ones (>40 years), but none for NCs. The number of NCs and MSCs was not different significantly between men and women. However, the patients with thoracolumbar fracture (TLF) had significantly more MSCs than those with degenerative disc disease (DDD), but not for NCs. On the other hand, enriched MSCs could adhere to the wall of porous beta-TCP within 2h combination, and proliferate well during culture in vitro. After 34.5 months, 95.1% cases had good spinal fusion results. None of the samples before grafting was positive in bacterial culture. Only four patients had a little exudation or moderate swelling in their wounds, and recovered with conservative treatment. PMID: 18639333 [PubMed - indexed for MEDLINE]
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Related Articles Biological treatment for degenerative disc disease: implications for the field of physical medicine and rehabilitation. Am J Phys Med Rehabil. 2008 Sep;87(9):694-702 Authors: Zhang Y, An HS, Tannoury C, Thonar EJ, Freedman MK, Anderson DG Abstract Spine care is a fast-growing sector of the outpatient practice for physiatrists. Current nonsurgical treatment modalities and surgical options for severe symptomatic intervertebral disc degeneration have limited and inconsistent clinical results. Thus, the development of novel approaches, such as biological treatments that offer the potential to halt or even reverse disc degeneration and restore physiologic disc function, are very attractive. In this article, we first review the structural changes that occur during intervertebral disc degeneration and their relationship with discogenic back pain. Subsequently, we review the treatment approaches currently under clinical trial and laboratory investigation. Physiatrists specializing in spine care have the skill set required for administering intradiscal injections and supervising a comprehensive rehabilitation program after the procedures. Ultimately, the clinical use of any biological treatment discussed herein would require the collective efforts of physicians (such as physiatrists and surgeons) and researchers (such as chemical and biomedical engineers, biologists, and chemists). PMID: 18716481 [PubMed - indexed for MEDLINE]
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Related Articles [Clinical study of lumbar fusion by hybrid construct of stem cells technique and biodegradable material]. Zhonghua Wai Ke Za Zhi. 2008 Apr 1;46(7):493-6 Authors: Zhang P, Gan YK, Tang J, Hao YQ, Wang Y, Sun YH, Zhu ZA, Dai KR Abstract OBJECTIVE: To explorer the effectiveness of enriched bone marrow stem cells technique for lumbar fusion. METHODS: With the randomization and control principles, 2 graft materials [Enrichment bone marrow mesenchymal stem cells hybridized with beta-tri calcium phosphate (composite graft group), autologous iliac crest bone graft (autograft group)] were compared in posterior lumbar fusion procedures. 56 patients with degenerative disc disease, lumbar instability or spinal stenosis, were included. The volume of cells suspension in pre- and post-enrichment and the number of nucleated cells (NCs) were identified. The number of osteoprogenitor cells was estimated by counting the colony-forming units which express alkaline phosphatase (CFUs/ALP+). Then the efficiency of the enrichment was evaluated. Clinical follow-up with roentgenogram and Oswestry scale scores was performed for outcome evaluation. RESULTS: (249 +/- 31) ml bone marrow per patient from bilateral iliac crests was aspirated peri-operatively. About (43 +/- 11) ml enriched bone marrow was collected. The number of NCs was concentrated from (15.9 +/- 3.3) x 10(6)/ml to (44.1 +/- 10.8) x 10(6)/ml, CFUs/ALP+ was significantly increased from (118 +/- 86)/ml to(486 +/- 305)/ml. The follow-up was about (26.3 +/- 7.5) months. There was no significant differences in age, gender, disease and fusion segments between the two groups. The fusion rate was 93.3% and 96.2% for composite graft group and autograft group, respectively (chi2 = 0.2146, P = 0.6432). There was no difference in operation time between the two group (t = 0.5243, P = 0.6022), but blood loss in composite graft group was more than that in autograft group (t = 6.4664, P < 0.01). Cell salvage for auto-transfusion could transfuse back half of the blood loss during operation. No hematoma or chronic soreness in the bone marrow donor sites of composite graft group occurred, but a little exudation or moderate swelling in the wound happened in 4 cases which disappeared under medical treatment. Meanwhile, 15.4% patients had hematoma in the iliac bone donor site and 26.9% patients had chronic soreness, but no case had wound problem in autograft group. As for Oswestry scale scores, there was no significant difference between the two groups. CONCLUSIONS: The enrichment technique of autologous bone marrow stem cells can greatly increase the concentration of MSCs. It is a rapid and safe method used peri-operatively. The composite material of enriched MSCs and porous beta-TCP is a good bone substitute in posterior spinal fusion. PMID: 18785556 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell applications in intervertebral disc repair. Cell Mol Biol (Noisy-le-grand). 2008;54(1):24-32 Authors: Hiyama A, Mochida J, Sakai D Abstract There is increasing rise of interest in stem cell therapy, as it provides new options for treating a broad range of diseases. Several experimental methods are being explored for the use of stem cells in delaying or reversing the degenerative process of the intervertebral disc, a major cause of low back pain. In this article, we review the current strategies for stem cell applications in intervertebral disc repair and present three novel approaches. These are, first, the activation of nucleus pulposus cells by co-culture with mesenchymal stem cells for autologous disc cell reinsertion; second, the in vitro induction of nucleus pulposus-like or annulus fibrosus-like cells from mesenchymal stem cells; and third, the in vivo induction study by direct transplantation of mesenchymal stem cells to the intervertebral disc induced to degenerate experimentally. Although still untested, stem cell therapy may become a major option in the treatment of intervertebral disc degeneration. PMID: 18954548 [PubMed - indexed for MEDLINE]
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Related Articles Tissue engineering and the intervertebral disc: the challenges. Eur Spine J. 2008 Dec;17 Suppl 4:480-91 Authors: Kandel R, Roberts S, Urban JP Abstract Disc degeneration is a common disorder. Although the back pain that can develop in association with this is rarely life-threatening, the annual cost in terms of morbidity, lost productivity, medical expenses and workers' compensation benefits is significant. Surgical intervention as practised currently is directed towards removing the damaged or altered tissue. Development of new treatment modalities is critical as there is a growing consensus that the strategies used currently for symptomatic degenerative disc disease may not be effective. Accordingly, there is a need to develop an entirely new way to treat this disorder; regenerative medicine and tissue engineering approaches appear particularly promising in this regard. This paper reviews some of the challenges that currently are limiting the clinical application of this approach to the treatment of disc degeneration. PMID: 19005701 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine (Phila Pa 1976). 2009 Jan 15;34(2):141-8 Authors: Henriksson HB, Svanvik T, Jonsson M, Hagman M, Horn M, Lindahl A, Brisby H Abstract STUDY DESIGN: Experimental and descriptive study of a xenotransplantation model in minipigs. OBJECTIVE: To study survival and function of human mesenchymal stem cells (hMSCs) after transplantation into injured porcine spinal discs, as a model for cell therapy. SUMMARY OF BACKGROUND DATA: Biologic treatment options of the intervertebral disc are suggested for patients with chronic low back pain caused by disc degeneration. METHODS: Three lumbar discs in each of 9 minipigs were injured by aspiration of the nucleus pulposus (NP), 2 weeks later hMSCs were injected in F12 media suspension (cell/med) or with a hydrogel carrier (Puramatrix) (cell/gel). The animals were sacrificed after 1, 3, or 6 months. Disc appearance was visualized by magnetic resonance imaging. Immunohistochemistry methods were used to detect hMSCs by antihuman nuclear antibody staining, and further performed for Collagen II, Aggrecan, and Collagen I. SOX 9, Aggrecan, Versican, Collagen IA, and Collagen IIA and Collagen IIB human mRNA expression was analyzed by real-time PCR. RESULTS: At magnetic resonance imaging all injured discs demonstrated degenerative signs. Cell/gel discs showed fewer changes compared with cell/med discs and only injured discs at later time points. hMSCs were detected in 9 of 10 of the cell/gel discs and in 8 of 9 of the cell/med discs. Immunostaining for Aggrecan and Collagen type II expression were observed in NP after 3 and 6 months in gel/cell discs and colocalized with the antihuman nuclear antibody. mRNA expression of Collagen IIA, Collagen IIB, Versican, Collagen 1A, Aggrecan, and SOX9 were detected in both cell/med and cell/gel discs at the time points 3 and 6 months by real-time PCR. CONCLUSION: hMSCs survive in the porcine disc for at least 6 months and express typical chondrocyte markers suggesting differentiation toward disc-like cells. As in autologous animal models the combination with a three-dimensional-hydrogel carrier seems to facilitate differentiation and survival of MSCs in the disc. Xenotransplantation seems to be valuable in evaluating the possibility for human cell therapy treatment for intervertebral discs. PMID: 19112334 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell horizons in intervertebral disc degeneration. Stem Cells Cloning. 2009;1:31-39 Authors: Ciacci J, Ho A, Ames CP, Jandial R Abstract Intervertebral disc degeneration remains a pervasive and intractable disease arising from a combination of aging and stress on the back and spine. The growing field of regenerative medicine brings the promise of stem cells in the treatment of disc disease. Scientists and physicians hope to employ stem cells not only to stop, but also reverse degeneration. However, there are many important outstanding issues, including the hostile avascular, apoptotic physiological environment of the intervertebral disc, and the difficulty of obtaining mesenchymal stem cells, and directing them towards chondrocytic differentiation and integration within the nucleus pulposus of the disc. Given the recent advances in minimally invasive spine surgery, and developing body of work on stem cell manipulation and transplantation, stem cells are uniquely poised to bring about large-scale improvements in treatment and outcomes for degenerative disc disease. In this review we will first discuss the cellular and molecular factors influencing degeneration, and then examine the efficacy and difficulties of stem cell transplantation. PMID: 24198503 [PubMed - as supplied by publisher]
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Related Articles MSC response to pH levels found in degenerating intervertebral discs. Biochem Biophys Res Commun. 2009 Feb 20;379(4):824-9 Authors: Wuertz K, Godburn K, Iatridis JC Abstract Painful degenerative disc disease is a major health problem and for successful tissue regeneration, MSCs must endure and thrive in a harsh disc microenvironment that includes matrix acidity as a critical factor. MSCs were isolated from bone marrow of Sprague-Dawley rats from two different age groups (<1 month, n=6 and 4-5 months, n=6) and cultured under four different pH conditions representative of the healthy, mildly or severely degenerated intervertebral disc (pH 7.4, 7.1, 6.8, and 6.5) for 5 days. Acidity caused an inhibition of aggrecan, collagen-1, and TIMP-3 expression, as well as a decrease in proliferation and viability and was associated with a change in cell morphology. Ageing had generally minor effects but young MSCs maintained greater mRNA expression levels. As acidic pH levels are typical of increasingly degenerated discs, our findings demonstrate the importance of early interventions and predifferentiation when planning to use MSCs for reparative treatments. PMID: 19133233 [PubMed - indexed for MEDLINE]
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Related Articles Biologic solutions for degenerative disk disease. J Spinal Disord Tech. 2009 Jun;22(4):297-308 Authors: Fassett DR, Kurd MF, Vaccaro AR Abstract STUDY DESIGN: Literature review. OBJECTIVE: Review the potential use of biologic therapies for the treatment of degenerative disk disease. SUMMARY OF BACKGROUND DATA: Degeneration of the intervertebral disk is a common occurrence which, although asymptomatic in most instances, may result in axial skeletal pain, radiculopathy, and myelopathy. Significant progress has been made in understanding the pathophysiology of degenerative disk disease and as a result, new biologic therapies, including molecular, gene, and cell-based strategies, are being investigated to halt and reverse disk degeneration. RESULTS: Growth factors, inflammatory inhibitors, proteinase inhibitors, and intracellular regulatory proteins are among the molecular therapies that have been studied with encouraging results in both in vitro and in vivo experiments. However, the utility of these therapies in humans may be limited because of the limited therapeutic duration. Gene therapies have the potential to overcome the limited therapeutic duration of molecular treatments by transferring genes to the cells within the disk to encode for therapeutic proteins with potential long-term local production. Gene therapy for disk regeneration has been successful in a number of animal studies, but significant concerns exist with the safety of the many vectors used for gene transfer. Cell-based therapies, including reimplantation of nucleus pulposus cells expanded in culture and stem cell therapies, have also been studied extensively in animal models with good results. The EuroDisc clinical trial is currently underway in Europe exploring the reimplantation of disk cells that are removed at the time of diskectomy and expanded ex vivo. Mesenchymal stem cells, which are readily available without ethical concerns, are being studied extensively for disk regeneration. Mesenchymal stem cells can differentiate into a phenotype similar to native nucleus pulposus cells and have shown the potential for disk regeneration in animal studies. CONCLUSIONS: Biologic therapies for intervertebral disk regeneration have produced very encouraging results in both in vitro and in vivo studies. Despite successful experimental results, these therapies face a number of hurdles before acceptance for human use including safety concerns, efficacy in high-order animal and human studies, and issues with the role and timing of these treatments. PMID: 19494751 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells arrest intervertebral disc degeneration through chondrocytic differentiation and stimulation of endogenous cells. Mol Ther. 2009 Nov;17(11):1959-66 Authors: Yang F, Leung VY, Luk KD, Chan D, Cheung KM Abstract Degenerative disc disease (DDD) is a common disease which affects millions of people. Autograft of the bone marrow derived mesenchymal stem cells (BMSCs) have been shown to have the ability to arrest degeneration in rabbit and canine intervertebral discs. In this study, we have used the mouse model to investigate the mechanism of degeneration arrest. BMSC from Egfp transgenic mice were injected into the degenerated murine intervertebral discs induced by annular puncture. We found that BMSC could arrest the progressive degeneration of the discs with significant regeneration of the nucleus pulposus (NP). In the regeneration, expression of proteoglycan genes were upregulated and extracellular matrix (ECM) progressively accumulated in the NP after BMSC injection. Combined in situ hybridization and immunohistochemistry revealed that BMSC underwent chondrocytic differentiation in the regeneration process. Interestingly, BMSC-induced an increase of endogenous notochordal cells in NP and expression of chondrocytic markers. In this study, we have firstly shown that the BMSC could arrest the degeneration of the murine notochordal NP and contribute to the augmentation of the ECM in the NP by both autonomous differentiation and stimulatory action on endogenous cells. PMID: 19584814 [PubMed - indexed for MEDLINE]
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Related Articles Nucleus pulposus tissue engineering: a brief review. Eur Spine J. 2009 Nov;18(11):1564-72 Authors: Yang X, Li X Abstract Symptomatic intervertebral disc degeneration is associated with several spinal diseases, which cause losses of life quality and money. Tissue engineering provides a promising approach to recover the functionality of the degenerative intervertebral disc. Most studies are directed toward nucleus pulposus (NP) tissue engineering because disc degeneration is believed to originate in NP region, and considerable progress has been made in the past decade. Before this important technique is utilized for clinical treatment of disc degeneration, many challenges need to address including in all three principal components of tissue engineering, i.e., seed cells, signals and biomaterial scaffolds. This article briefly gives certain aspects of state of the art in this field, as well as pays a little more attention to our work published in the past 5 years, on growth and differentiation factor-5 (GDF-5), adipose-derived stem cells (ADSCs) and heparin functionalization of scaffold. We suggest that combinatorial application of ADSCs, GDF-5, heparin functionalization and injectable hydrogels will be advantageous in NP tissue engineering. PMID: 19603198 [PubMed - indexed for MEDLINE]
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Related Articles Intervertebral disc regeneration in an ex vivo culture system using mesenchymal stem cells and platelet-rich plasma. Biomaterials. 2009 Oct;30(29):5523-33 Authors: Chen WH, Liu HY, Lo WC, Wu SC, Chi CH, Chang HY, Hsiao SH, Wu CH, Chiu WT, Chen BJ, Deng WP Abstract An ex vivo degenerative intervertebral disc (IVD) organ culture system was established for the screening of disc regeneration agents. Its application was demonstrated by a stem cell and growth factor-based therapeutic approach for the amelioration of IVD. An ex vivo culture system using chymopapain to partially digest nucleus proposus tissue was established to mimic human IVD degeneration. This system was then used for the evaluation of different therapeutic regimens including: mesenchymal stem cell derived from eGFP-transgenic porcine (MSC-GFP), platelet-rich plasma (PRP) and MSC-GFP/PRP combined treatment, and confirmed in in vivo animal model. Chondrogenic-specific gene products including Col II and aggrecan were found upregulated and chondrogenic matrix deposition increased, as evident by sustained fluorescent signals over 4 weeks, in the MSC-GFP implanted group. Previously, we demonstrated in vitro stage-specific chondrogenesis of MSC by chondrocytic commitment. These same molecules upregulated for chondrogenesis were also observed in MSC-GFP group. PRP that has been shown to promote nucleus pulposus (NP) regeneration also resulted in significant increased levels of mRNA involved in chondrogenesis and matrices accumulation. The ex vivo IVD regeneration results were repeated and supported by in vivo porcine degenerative system. Moreover, the disc height index (DHI) was significantly increased in both in vivo MSC-GFP and PRP regeneration groups. Unexpectedly, the MSC-GFP/PRP combined therapy demonstrated an inclination towards osteogenesis in ex vivo system. The ex vivo degenerative IVD culture system described in this study could serve as an alternative and more accessible model over large animal model. This system also provides a high-throughput platform for screening therapeutic agents for IVD regeneration. PMID: 19646749 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol. 2010 Jan;222(1):23-32 Authors: Richardson SM, Hoyland JA, Mobasheri R, Csaki C, Shakibaei M, Mobasheri A Abstract Defects of load-bearing connective tissues such as articular cartilage and intervertebral disc (IVD) can result from trauma, degenerative, endocrine, or age-related disease. Current surgical and pharmacological options for the treatment of arthritic rheumatic conditions in the joints and spine are ineffective. Cell-based surgical therapies such as autologous chondrocyte transplantation (ACT) have been in clinical use for cartilage repair for over a decade but this approach has shown mixed results. This review focuses on the potential of mesenchymal stem cells (MSCs) as an alternative to cells derived from patient tissues in autologous transplantation and tissue engineering. Here we discuss the prospects of using MSCs in regenerative medicine and summarize the advantages and disadvantages of these cells in articular cartilage and IVD tissue engineering. We discuss the conceptual and practical difficulties associated with differentiating and pre-conditioning MSCs for subsequent survival in a physiologically harsh extracellular matrix, an environment that will be highly hypoxic, acidic, and nutrient deprived. Implanted MSCs will be exposed to traumatic physical loads and high levels of locally produced inflammatory mediators and catabolic cytokines. We also explore the potential of culture models of MSCs, fully differentiated cells and co-cultures as "proof of principle" ethically acceptable "3Rs" models for engineering articular cartilage and IVD in vitro for the purpose of replacing the use of animals in arthritis research. PMID: 19725073 [PubMed - indexed for MEDLINE]
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Related Articles [New perspectives on degenerative disease treatment]. Acta Reumatol Port. 2009 Apr-Jun;34(2B):327-35 Authors: da Silva MR, Domingues CJ, Pinto RP, Neves N, Matos RM, Tulha JM, Cabral AT Abstract The degenerative disc disease (DDD) is a chronic and multifactorial condition of the intervertebral disc that can manifest itself by axial pain, radiculopathy, myelopathy and spinal stenosis. It constitutes an increasing cause of lumbar pain and morbidity in Western Societies, with important socio-economic implications. The available treatment options do not modify the intervertebral disc degeneration process and they are not always capable of relieving symptoms. The loss of proteoglycan content of nucleus pulposus appears to be the main event on DDD pathophysiology. The balance between synthesis and catabolism of the extracellular matrix can be altered by the use of several proteins, including growth factors. The transfer of genes encoding these proteins is an attractive treatment option and has been successfully achieved in animal models. Moreover, the transfer of steam cells in order to repopulate the degenerated disc and to revert the pathologic process might be another promissory strategy. The authors describe the actual knowledge about DDD and the investigation that has been made in gene therapy for DDD. The comprehension of the biological mechanisms of degeneration, as well as genetic manipulation and transfer of steam cells could be decisive and revolutionary in the understanding and treatment of this epidemic condition. PMID: 19727045 [PubMed - indexed for MEDLINE]
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Related Articles Effects of implantation of bone marrow mesenchymal stem cells, disc distraction and combined therapy on reversing degeneration of the intervertebral disc. J Bone Joint Surg Br. 2010 May;92(5):726-36 Authors: Hee HT, Ismail HD, Lim CT, Goh JC, Wong HK Abstract Although success has been achieved with implantation of bone marrow mesenchymal stem cells (bMSCs) in degenerative discs, its full potential may not be achieved if the harsh environment of the degenerative disc remains. Axial distraction has been shown to increase hydration and nutrition. Combining both therapies may have a synergistic effect in reversing degenerative disc disease. In order to evaluate the effect of bMSC implantation, axial distraction and combination therapy in stimulating regeneration and retarding degeneration in degenerative discs, we first induced disc degeneration by axial loading in a rabbit model. The rabbits in the intervention groups performed better with respect to disc height, morphological grading, histological scoring and average dead cell count. The groups with distraction performed better than those without on all criteria except the average dead cell count. Our findings suggest that bMSC implantation and distraction stimulate regenerative changes in degenerative discs in a rabbit model. PMID: 20436013 [PubMed - indexed for MEDLINE]
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Related Articles Regeneration of intervertebral discs in a rat disc degeneration model by implanted adipose-tissue-derived stromal cells. Acta Neurochir (Wien). 2010 Oct;152(10):1771-7 Authors: Jeong JH, Lee JH, Jin ES, Min JK, Jeon SR, Choi KH Abstract BACKGROUND: Because adipose-tissue-derived stromal cell (ADSC) is readily accessible and abundant in stem cell, ADSC may be a better candidate for cell therapy and tissue engineering. This study investigated the potential of ADSC implantation to restore disc in a rat IVD model. METHODS: The first coccygeal disc segments of a Sprague-Dawley rat was left undamaged as a control (NC) group, and other two segments were damaged by needle injection. Two weeks later, ADSCs (TS) group or saline (IN) group was transplanted into each of the two damaged segments. RESULTS: At 6 weeks after transplantation, the TS group showed a significantly smaller reduction in disc height than the IN group and exhibited a restoration of MRI signal intensity. Hematoxylin and eosin staining revealed a greater restoration of the inner annulus structure in the TS group. Anti-Human Nucleic Antibody, collagen type II, and aggrecan, staining showed positive findings at 2 weeks after transplantation in TS group. CONCLUSIONS: ADSCs show potential for restoring degenerative discs and may prove effective in the treatment of IVD. PMID: 20571835 [PubMed - indexed for MEDLINE]
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Related Articles Isolation and characterization of mesenchymal stromal cells from human degenerated nucleus pulposus: comparison with bone marrow mesenchymal stromal cells from the same subjects. Spine (Phila Pa 1976). 2010 Dec 15;35(26):2259-65 Authors: Blanco JF, Graciani IF, Sanchez-Guijo FM, Muntión S, Hernandez-Campo P, Santamaria C, Carrancio S, Barbado MV, Cruz G, Gutierrez-Cosío S, Herrero C, San Miguel JF, Briñon JG, del Cañizo MC Abstract STUDY DESIGN: To identify mesenchymal stromal cells (MSC) from degenerate human nucleus pulposus (NP) and compare them with bone marrow (BM) MSC. OBJECTIVE: To test whether MSC obtained from NP and BM from the same subjects share similar biologic characteristics. SUMMARY OF BACKGROUND DATA: Recent studies have proposed biologic strategies for the treatment of intervertebral disc degeneration, including cell therapy. Bone marrow (BM) MSC could be an attractive approach to restore disc function, and there is evidence that NP may contain MSC-like cells. METHODS: Tissue samples were obtained from degenerate lumbar NP and from iliac crest of the same 16 patients with degenerative disc diseases, undergoing discectomy and fusion procedures. MSC isolated from both sources were compared regarding their expansion time, immunophenotype, differentiation ability, and molecular analysis. RESULTS: In all cases, MSC from NP were isolated and expanded. They fulfil nearly all morphological, inmunophenotypical, and differentiation criteria described by the International Society of Cell Therapy for MSC, with the exception that NP-MSC are not able to differentiate into adipocytes. Slight differences were observed with BM-MSC from the same subjects. CONCLUSION: The NP contains mesenchymal stem cells. These cells were quite similar to mesenchymal stem cells from BM, with the exception of their adipogenic differentiation ability. These findings suggest that we may treat intervertebral disc degeneration by cell therapy (MSC from BM) and by stimulating endogenous MSC from NP. PMID: 20622750 [PubMed - indexed for MEDLINE]
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Related Articles Transplanted mesenchymal stem cells with pure fibrinous gelatin-transforming growth factor-beta1 decrease rabbit intervertebral disc degeneration. Spine J. 2010 Sep;10(9):802-10 Authors: Yang H, Wu J, Liu J, Ebraheim M, Castillo S, Liu X, Tang T, Ebraheim NA Abstract BACKGROUND CONTEXT: Disc degeneration is a major reason for low back pain and can be caused by apoptosis. The prevention of apoptosis using mesenchymal stem cells (MSCs) may lead to new treatments for low back pain. Previous studies have reported that transplanted MSCs can proliferate and differentiate into cells expressing some of the major phenotypic qualities of nucleus pulposus cells. However, the effects of MSC transplantation on the disc height index (DHI) and apoptosis inhibition have not yet been thoroughly investigated. PURPOSE: The present study evaluates the effects of MSC transplantation on DHI and its potential to inhibit apoptosis. STUDY DESIGN/SETTING: Random, controlled, animal experiment study. METHODS: The annulus fibrosus of 54 white New Zealand rabbits was punctured with a 21-gauge needle, and the nucleus pulposus tissue from the intervertebral discs was aspirated. The degenerative disc model was produced in each rabbit, which were then randomly divided into three groups: degenerative model group; pure fibrinous gelatin-transforming growth factor-beta1 (PFG-TGF-beta1) transplanted group; and MSC-PFG-TGF-beta1 transplanted group. Computed radiography imaging, magnetic resonance imaging, and histological examinations were performed at Weeks 4, 8, and 12. RESULTS: The transplanted MSCs inhibited apoptosis and slowed the rate of decrease in DHI. Magnetic resonance imaging results showed that the MSC-PFG-TGF-beta1 group had less degeneration and a slower decrease in DHI compared with both the degenerative model and PFG-TGF-beta1 groups. An increased quantity of nucleus pulposus and type II collagen content and a decrease in the rate of cell apoptosis were noted in the MSC-PFG-TGF-beta1 group. CONCLUSIONS: Mesenchymal stem cells can slow the rate at which the DHI decreases. This effect may be because of the inhibition of apoptosis by MSCs. PMID: 20655810 [PubMed - indexed for MEDLINE]
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Related Articles Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res. 2010 Oct;28(10):1267-75 Authors: Serigano K, Sakai D, Hiyama A, Tamura F, Tanaka M, Mochida J Abstract Transplantation of mesenchymal stem cells (MSCs) inhibits the progression of disc degeneration in animal models. We know of no study to determine the optimal number of cells to transplant into the degenerated intervertebral disc (IVD). To determine the optimal donor cell number for maximum benefit, we conducted an in vivo study using a canine disc degeneration model. Autologous MSCs were transplanted into degenerative discs at 10(5), 10(6), or 10(7) cells per disc. The MSC-transplanted discs were evaluated for 12 weeks using plain radiography, magnetic resonance imaging, and gross and microscopic evaluation. Preservation of the disc height, annular structure was seen in MSC-transplantation groups compared to the operated control group with no MSC transplantation. Result of the number of remaining transplanted MSCs, the survival rate of NP cells, and apoptosis of NP cells in transplanted discs showed both structural microenvironment and abundant extracellular matrix maintained in 10(6) MSCs transplanted disc, while less viable cells were detected in 10(5) MSCs transplanted and more apoptotic cells in 10(7) MSCs transplanted discs. The results of this study demonstrate that the number of cells transplanted affects the regenerative capability of MSC transplants in experimentally induced degenerating canine discs. It is suggested that maintenance of extracellular matrix by its production from transplanted cells and/or resident cells is important for checking the progression of structural disruption that leads to disc degeneration. PMID: 20839317 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of mesenchymal stem cells and nucleus pulposus cells in a degenerative disc model in rabbits: a comparison of 2 cell types as potential candidates for disc regeneration. J Neurosurg Spine. 2011 Mar;14(3):322-9 Authors: Feng G, Zhao X, Liu H, Zhang H, Chen X, Shi R, Liu X, Zhao X, Zhang W, Wang B Abstract OBJECT: The aim of this study was to compare transplanted mesenchymal stem cells (MSCs) with nucleus pulposus cells (NPCs) in a degenerative disc model in rabbits to determine the better candidate for disc cell therapy. METHODS: Mesenchymal stem cells and NPCs were transplanted in a rabbit model of disc degeneration. Changes in disc height, according to plain radiography, T2-weighted signal intensity on MR imaging, histology, sulfated glycosaminoglycan (sGAG)/DNA, and associated gene expression levels, were evaluated among healthy controls without surgery, sham-operated animals in which only disc degeneration was induced, MSC-transplanted animals, and NPC-transplanted animals for a 16-week period. RESULTS: Sixteen weeks after cell transplantation, in the MSC- and NPC-transplanted groups, the decline in the disc height index was reduced and T2-weighted signal intensity increased compared with the sham-operated group. Safranin O staining showed a high GAG content, which was also supported by sGAG/DNA assessment. Disc regeneration was also confirmed at the gene expression level using real-time polymerase chain reaction. However, no significant differences in expression were found between the NPC- and MSC-transplanted groups. CONCLUSIONS: Study data showed that MSC transplantation is effective for the treatment of disc degeneration and seems to be an ideal substitute for NPCs. PMID: 21250814 [PubMed - indexed for MEDLINE]
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Related Articles Autologous stem cell therapy maintains vertebral blood flow and contrast diffusion through the endplate in experimental intervertebral disc degeneration. Spine (Phila Pa 1976). 2011 Mar 15;36(6):E373-9 Authors: Bendtsen M, Bünger CE, Zou X, Foldager C, Jørgensen HS Abstract STUDY DESIGN: Experimental, controlled, randomized, and paired study. OBJECTIVE: To evaluate regenerative effect of stem cell therapy on the vertebral endplate and introduce dynamic contrast-enhanced magnetic resonance imaging (MRI) as a tool in the investigation of endplate function. SUMMARY OF BACKGROUND DATA: The vertebral endplate plays a crucial role in nutritional supply to the intervertebral disc. Estimation of endplate function is an important parameter in future biologic therapy of intervertebral disc degeneration (IDD). METHODS: Four-level IDD was induced in each of 15 Gottingen minipigs. Percutaneous intradiscal injection of two hydrogels (Zimmer Biologics Inc, Austin, TX) and one loaded with stem cells was used as single interventions after 12 weeks. Total observation time was 24 weeks. MRI was performed before the initiation of treatment and killing of animals. RESULTS: Three animals were excluded because of spondylodiscitis. Stem cell and hydrogel treatment had significantly higher T2 values, relative vertebral blood flow and volume, as well as lower Pfirrmann scores when compared with degenerative controls. No statistical differences were found compared to normal controls. CONCLUSION: Stem cell and hydrogel therapy is able to partly regenerate IDD and maintain perfusion and permeability of the vertebral endplate and subchondral bone. Dynamic contrast-enhanced MRI may become an important tool in future investigation of the vertebral endplate. PMID: 21372649 [PubMed - indexed for MEDLINE]
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Related Articles Sox-9 facilitates differentiation of adipose tissue-derived stem cells into a chondrocyte-like phenotype in vitro. J Orthop Res. 2011 Aug;29(8):1291-7 Authors: Yang Z, Huang CY, Candiotti KA, Zeng X, Yuan T, Li J, Yu H, Abdi S Abstract The purpose of this study is to test whether ectopic expression of Sox-9 can induce adipose tissue-derived stem cells (ASCs) to function as real nucleus pulposus (NP) cells in vitro. Adenoviral vectors expressing Sox-9 were reported to infect the chondroblastic and human disc cells, which resulted in increased Sox-9 and type II collagen production. ASCs were isolated from rat inguinal adipose pad, characterized, and transduced in vitro with a retroviral vector encoding the Sox-9 gene. Sox-9-engineered ASCs (ASCs/Sox-9) were induced for the chondrocyte-like cell differentiation by 3D cultured in alginate beads and TGF-β3 for 2 weeks. Expression of exogenous Sox-9 protein was detected. Type II collagen and Aggrecan gene expressions of induced ASCs/Sox-9 were measured using real-time PCR; proteoglycans expressions were measured by checking the glycosaminoglycan content and type II collagen production by enzyme-linked immunosorbent assay. Isolated ASCs were CD 29(+) /CD44(+) /C-Kit(-) /Lin(-) /CD34(-) /CD45(-) . ASCs/Sox-9 expressed marked increase in exogenous Sox-9 protein. After induction, type II collagen gene expression was sevenfold higher in mRNA levels, with an approximately twofold increase in protein levels of ASCs/Sox-9 compared to ASCs. Type II collagen and proteoglycan productions were significantly increased in the ASCs/Sox-9 compared to the ASCs. In addition, co-culture of induced ASCs/Sox-9 with matured NP cells resulted in enhanced increase in proteoglycan and type II collagen production. Constitutive retroviral expression of Sox-9 could efficiently induce ASCs differentiation into chondrocyte-like cells. This novel approach may provide a practicable system for a simple and rapid differentiation of ASCs into chondrocyte-like cells which may be potentially used as a stem cell-based therapeutic tool for the treatment of degenerative disc diseases. PMID: 21400575 [PubMed - indexed for MEDLINE]
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Related Articles Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation. 2011 Oct 15;92(7):822-8 Authors: Orozco L, Soler R, Morera C, Alberca M, Sánchez A, García-Sancho J Abstract BACKGROUND: Degenerative disc disease may cause severe low-back pain, a large public health problem with significant economic and life quality impact. Chronic cases often require surgery, which may lead to biomechanical problems and accelerated degeneration of the adjacent segments. Cell-based therapies may circumvent these problems and have exhibited encouraging results in vitro and in animal studies. We designed a pilot study to assess feasibility and safety and to obtain early indications on efficacy of treatment with mesenchymal stem cells (MSC) in humans. METHODS: Ten patients with chronic back pain diagnosed with lumbar disc degeneration with intact annulus fibrosus were treated with autologous expanded bone marrow MSC injected into the nucleus pulposus area. Clinical evolution was followed for 1 year and included evaluation of back pain, disability, and quality of life. Magnetic resonance imaging measurements of disc height and fluid content were also performed. RESULTS: Feasibility and safety were confirmed and strong indications of clinical efficacy identified. Patients exhibited rapid improvement of pain and disability (85% of maximum in 3 months) that approached 71% of optimal efficacy. This outcome compares favorably with the results of other procedures such as spinal fusion or total disc replacement. Although disc height was not recovered, water content was significantly elevated at 12 months. CONCLUSIONS: MSC therapy may be a valid alternative treatment for chronic back pain caused by degenerative disc disease. Advantages over current gold standards include simpler and more conservative intervention without surgery, preservation of normal biomechanics, and same or better pain relief. PMID: 21792091 [PubMed - indexed for MEDLINE]
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Related Articles Three-dimensional culture of rabbit nucleus pulposus cells in collagen microspheres. Spine J. 2011 Oct;11(10):947-60 Authors: Yuan M, Leong KW, Chan BP Abstract BACKGROUND: Degenerative disc disease poses an increasing threat to our quality of life as we age. Existing treatments have limitations. New treatment modalities focusing on biologic rather than surgical approach would be appealing. PURPOSE: Culturing intervertebral disc cells in a three-dimensional (3D) model that can retain cellular characteristics and phenotype is a critical step toward understanding how the disc cells respond to and interact with extrinsic signals before better therapeutics can be derived. STUDY DESIGN: In this work, we studied the culture of rabbit nucleus pulposus (NP) cells in a collagen microsphere system and compared their cell morphology and expression of a few potential phenotypic markers with that in monolayer culture. METHODS: Specifically, rabbit NP cells isolated from both young and old animals were encapsulated and cultured in collagen microspheres with different monomeric concentrations and with different cell encapsulation density for different period of time. Evaluation on the growth kinetics, the viability, the cell morphology, the expression of Types I and II collagen, glycosaminoglycans (GAGs), and Keratin 19, and the ultrastructure of the fiber meshwork were conducted to compare the microsphere 3D culture system and the traditional monolayer cultures. RESULTS: Nucleus pulposus cells in two-dimensional culture lost the phenotypic expression of Type II collagen and keratin 19 and expressed Type I collagen. In contrast, the 3D collagen microsphere culture system consistently outperformed the traditional monolayer culture in maintaining a round morphology and preserving the phenotypes of NP cells with persistent expression of Type II collagen and Keratin 19. These cells also remodeled the template collagen matrix in the microspheres by depositing new matrices, including collagen Type II and GAGs in a cell seeding density and collagen concentration dependent manner. CONCLUSIONS: This study demonstrates the appeal of the 3D collagen microsphere system for NP cell culture over traditional monolayer culture because it preserves the phenotypic characteristics of NP cells. This system also enables the NP cells to remodel the template collagen matrix by depositing new matrices, suggesting an innovative way to reconstitute cell-specific and native tissue-like environment in vitro for future studies on stem cell matrix niche and interactions of NP cell with extrinsic factors. PMID: 21843975 [PubMed - indexed for MEDLINE]
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Related Articles Intervertebral disk degeneration and emerging biologic treatments. J Am Acad Orthop Surg. 2011 Sep;19(9):543-53 Authors: Kepler CK, Anderson DG, Tannoury C, Ponnappan RK Abstract Although understanding of the biologic basis of intervertebral disk (IVD) degeneration is rapidly advancing, the unique IVD environment presents challenges to the development and delivery of biologic treatments. Acceleration of cellular senescence and apoptosis in degenerative IVDs and the depletion of matrix proteins have prompted the development of treatments based on replacing IVD cells using various cell sources. However, this strategy has not been tested in animal models. IVD degeneration and associated pain have led to interest in pathologic innervation of the IVD and ultimately to the development of percutaneous devices to ablate afferent nerve endings in the posterior annulus. Degeneration leads to changes in the expression of matrix protein, cytokines, and proteinases. Injection of growth factors and mitogens may help overcome these degenerative changes in IVD phenotype, and these potential treatments are being explored in animal studies. Gene therapy is an elegant method to address changes in protein expression, but efforts to apply this technology to IVD degeneration are still at early stages. PMID: 21885700 [PubMed - indexed for MEDLINE]
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Related Articles Structured bilaminar coculture outperforms stem cells and disc cells in a simulated degenerate disc environment. Spine (Phila Pa 1976). 2012 May 1;37(10):813-8 Authors: Allon AA, Butcher K, Schneider RA, Lotz JC Abstract STUDY DESIGN: This study explores the use of bilaminar coculture pellets of mesenchymal stem cells (MSCs) and nucleus pulposus cells (NPCs) as a cell-based therapy for intervertebral disc regeneration. The pellets were tested under conditions that mimic the degenerative disc. OBJECTIVE: Our goal was to optimize our cell-based therapy in vitro under conditions representative of the eventual diseased tissue. SUMMARY OF BACKGROUND DATA: Harnessing the potential of stem cells is an important strategy for regenerative medicine. Our approach directed the behavior of stem cells by mimicking embryonic processes underlying cartilage and intervertebral disc development. Prior experiments have shown that bilaminar coculture can help differentiate MSC and substantially improve new matrix deposition. METHODS: We have designed a novel spherical bilaminar cell pellet (BCP) where MSCs are enclosed in a shell of NPC. There were 3 groups: MSC, NPC, and BCP. The pellets were tested under 3 different culture conditions: 1) in a bioreactor that provides pressure and hypoxia (mimicking normal disc conditions): 2) with inflammatory cytokines (IL-1b and TNF-a); and 3) a bioreactor with inflammation (mimicking painful disc conditions). RESULTS: When cultured in the bioreactor, the NPC pellets produced significantly more glycosaminoglycans (GAGs) per cell than the other groups: 70% to 80% more than the BCP and the MSC alone. When cultured in an inflammatory environment, the MSC and BCP groups produced 30% to 34% more GAGs per cell than NPC (P < 0.05). When the pellets were cultured in a bioreactor with inflammation, the BCP made 25% more GAGs per cell than the MSC and 57% more than the NPC (P < 0.05). CONCLUSION: This study shows that BCPs outperform controls in a simulated degenerated disc environment. Adapting inductive mechanisms from development to trigger differentiation and restore diseased tissue has many advantages. As opposed to strategies that require growth factor supplements or genetic manipulations, our method is self-sustaining, targeted, and minimally invasive injection. PMID: 22024902 [PubMed - indexed for MEDLINE]
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Related Articles Study to determine the presence of progenitor cells in the degenerated human cartilage endplates. Eur Spine J. 2012 Apr;21(4):613-22 Authors: Huang B, Liu LT, Li CQ, Zhuang Y, Luo G, Hu SY, Zhou Y Abstract INTRODUCTION: Cartilage endplate (CEP) degeneration is usually accompanied by loss of cellularity, and this loss may be a crucial key factor in initiation and development of degenerative disc disease. The study of cell types in degenerated CEP could help in understanding CEP etiopathogenesis, and may help in devising new treatments, especially if the presence of progenitor cells could be demonstrated. The aim of this study was to determine if progenitor cells existed in degenerated human CEP. MATERIALS AND METHODS: Cells isolated from CEP were cultured in a three-dimensional agarose suspension to screen for proliferative cell clusters. Cell clusters were then expanded in vitro and the populations were analyzed for colony forming unit, immunophenotype, multilineage induction, and expression of stem cell-related genes. RESULTS: The presence of progenitor cells in degenerated human CEP is indicated by the results of CFU, immunophenotype, multilineage induction, and expression of stem cell-related genes. CONCLUSIONS: We believe that this is the first study which has conclusively shown the presence of progenitor cells in degenerated CEP. The finding of this study may influence the clinical management of degenerative disc disorder. PMID: 22033570 [PubMed - indexed for MEDLINE]
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Related Articles Evaluation of platelet-rich plasma and hydrostatic pressure regarding cell differentiation in nucleus pulposus tissue engineering. J Tissue Eng Regen Med. 2013 Mar;7(3):244-52 Authors: Mietsch A, Neidlinger-Wilke C, Schrezenmeier H, Mauer UM, Friemert B, Wilke HJ, Ignatius A Abstract Generation of a biological nucleus pulposus (NP) replacement by tissue engineering appears to be a promising approach for the therapy of early stages of intervertebral disc degeneration. Thereby, autologous mesenchymal stem cells (MSCs) represent an attractive cell source compared to cells of the NP that are already altered in their phenotype due to degenerative processes. This study compares the influence of 3D pellet culture and alginate beads, as well as that of different media compositions, by the addition of human platelet-rich plasma (PRP) or transforming growth factor (TGF-β1 ) in interaction with hydrostatic pressure on chondrogenic differentiation of human MSCs compared to NP cells. We found that gene expression of the chondrogenic markers aggrecan, collagen type 2 and collagen type 1 and Sox9 was considerably lower in cells cultivated with PRP compared to TGF-β1 . Immunohistology confirmed this result at protein level in pellet culture. Additionally, the pellet culture system was found to be more suitable than alginate beads. A positive influence of hydrostatic pressure could only be shown for individual donors. In summary, in comparison to TGF-β1 , human PRP did not induce adequate chondrogenic differentiation for both culture systems and cell types used. The mixture of growth factors in PRP promoted proliferation rather than chondrogenic differentiation. Based on these results, an application of PRP in human NP tissue-engineering approaches cannot be recommended. Copyright © 2011 John Wiley & Sons, Ltd. PMID: 22162329 [PubMed - in process]
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Related Articles Transplantation of human adipose-derived stem cells in a rabbit model of traumatic degeneration of lumbar discs. World Neurosurg. 2012 Sep-Oct;78(3-4):364-71 Authors: Chun HJ, Kim YS, Kim BK, Kim EH, Kim JH, Do BR, Hwang SJ, Hwang JY, Lee YK Abstract OBJECTIVE: The purpose of the present study is to assess the possibility of disc regeneration by treatment with adipose-derived stem cells (ADSCs) in a rabbit model of degenerative disc disease, and to evaluate the efficacy of a percutaneous technique for constructing a model of degenerative disc disease in rabbits. METHODS: The study sample consisted of 20 mature male New Zealand white rabbits. Intervertebral discs were injured in each rabbit by a percutaneous technique at L2-3, L3-4, and L4-5 under C-arm guidance with a 19-gauge spinal needle. Magnetic resonance images (MRI) were checked at 6, 9, 12, and 15 weeks after injury to evaluate disc degeneration. Nineteen weeks after injury, ADSCs were injected into the L4-5 disc space, with saline injected into the L3-4 disc as a control, using a 21-gauge spinal needle. Histologic confirmations of degenerated discs were performed at 10 and 18 weeks after injury with safranin O and trichrome stains. RESULTS: MRI revealed intervertebral disc degeneration from 9 weeks after injury, and full degeneration at 15 weeks after injury, when compared with uninjured control discs. We confirmed the proliferation of ADSCs at the L4-5 level in 10-week rabbits after cell injection. Histologically, the ADSC-injected discs exhibited elevated extracellular matrix secretion and little ossification of damaged cartilage in the nucleus pulposus compared with degenerative control discs. CONCLUSIONS: These results suggest that the injection of ADSCs into injured lumbar discs could be an effective treatment for degenerative disc disease by promoting the cartilage regeneration. PMID: 22381275 [PubMed - indexed for MEDLINE]
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Related Articles Homing of mesenchymal stem cells in induced degenerative intervertebral discs in a whole organ culture system. Spine (Phila Pa 1976). 2012 Oct 15;37(22):1865-73 Authors: Illien-Jünger S, Pattappa G, Peroglio M, Benneker LM, Stoddart MJ, Sakai D, Mochida J, Grad S, Alini M Abstract STUDY DESIGN: Homing of human bone marrow-derived mesenchymal stem cells (BMSCs) was studied using ex vivo cultured bovine caudal intervertebral discs (IVDs). OBJECTIVE: To investigate in a whole organ culture whether metabolic and mechanical challenges can induce BMSC recruitment into the IVD. SUMMARY OF BACKGROUND DATA: Cells from injured tissues release cytokines and mediators that enable the recruitment of progenitor cells. BMSCs have the ability to survive within the IVD. METHODS: Bovine IVDs with or without endplates were cultured for 1 week under simulated physiological or degenerative conditions; disc cells were analyzed for cell viability and gene expression, whereas media was analyzed for nitric oxide production and chemotaxis. Homing of BMSCs was investigated by supplying PKH-labeled human BMSCs onto cultured IVDs (1 × 10(6) cells/disc on d 8, 10, and 12 of culture); on day 14, the number of homed BMSCs was microscopically assessed. Moreover, a comparative study was performed between transduced BMSCs (transduced with an adenovirus encoding for insulin-like growth factor 1 [IGF-1]) and nontransduced BMSCs. Disc proteoglycan synthesis rate was quantified via (35)S incorporation. The secretion of IGF-1 was evaluated by enzyme-linked immunosorbent assay on both simulated physiological and degenerative discs. RESULTS: Discs cultured under degenerative conditions showed reduced cell viability, upregulation of matrix degrading enzymes, and increased nitric oxide production compared with simulated physiological discs. Greater homing occurred under degenerative compared with physiological conditions with or without endplate. Media of degenerative discs demonstrated a chemoattractive activity toward BMSCs. Finally, discs homed with IGF-1-transduced BMSCs showed increased IGF-1 secretion and significantly higher proteoglycan synthesis rate than discs supplied with nontransduced BMSCs. CONCLUSION: We have demonstrated for the first time that degenerative conditions induce the release of factors promoting BMSC recruitment in an ex vivo organ culture. Moreover, IGF-1 transduction of BMSCs strongly increases the rate of proteoglycan synthesis within degenerative discs. This finding offers a new delivery system for BMSCs and treatment strategy for IVD regeneration. PMID: 22433498 [PubMed - indexed for MEDLINE]
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Related Articles Lumbar degenerative disc disease: current and future concepts of diagnosis and management. Adv Orthop. 2012;2012:970752 Authors: Taher F, Essig D, Lebl DR, Hughes AP, Sama AA, Cammisa FP, Girardi FP Abstract Low back pain as a result of degenerative disc disease imparts a large socioeconomic impact on the health care system. Traditional concepts for treatment of lumbar disc degeneration have aimed at symptomatic relief by limiting motion in the lumbar spine, but novel treatment strategies involving stem cells, growth factors, and gene therapy have the theoretical potential to prevent, slow, or even reverse disc degeneration. Understanding the pathophysiological basis of disc degeneration is essential for the development of treatment strategies that target the underlying mechanisms of disc degeneration rather than the downstream symptom of pain. Such strategies ideally aim to induce disc regeneration or to replace the degenerated disc. However, at present, treatment options for degenerative disc disease remain suboptimal, and development and outcomes of novel treatment options currently have to be considered unpredictable. PMID: 22567411 [PubMed]
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Related Articles Stem cell therapy for degenerative disc disease. Adv Orthop. 2012;2012:961052 Authors: Drazin D, Rosner J, Avalos P, Acosta F Abstract Low back pain is widely recognized as one of the most prevalent pathologies in the developed world. In the United States, low back pain is the most common health problem for adults under the age of 50, resulting in significant societal and personal costs. While the causes of low back pain are myriad, it has been significantly associated with intervertebral disc (IVD) degeneration. Current first-line therapies for IVD degeneration such as physical therapy and spinal fusion address symptoms, but do not treat the underlying degeneration. The use of tissue engineering to treat IVD degeneration provides an opportunity to correct the pathological process. Novel techniques are currently being investigated and have shown mixed results. One major avenue of investigation has been stem cell injections. Mesenchymal stem cells (MSCs) have shown promise in small animal models, but results in larger vertebrates have been mixed. PMID: 22593830 [PubMed]
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Related Articles Diversity of intervertebral disc cells: phenotype and function. J Anat. 2012 Dec;221(6):480-96 Authors: Pattappa G, Li Z, Peroglio M, Wismer N, Alini M, Grad S Abstract The intervertebral disc (IVD) is a moderately moving joint that is located between the bony vertebrae and provides flexibility and load transmission throughout the spinal column. The disc is composed of different but interrelated tissues, including the central highly hydrated nucleus pulposus (NP), the surrounding elastic and fibrous annulus fibrosus (AF), and the cartilaginous endplate (CEP), which provides the connection to the vertebral bodies. Each of these tissues has a different function and consists of a specific matrix structure that is maintained by a cell population with distinct phenotype. Although the healthy IVD is able to balance the slow matrix turnover of synthesis and degradation, this balance is often disturbed, leading to degenerative disorders. Successful therapeutic management of IVD degeneration requires a profound understanding of the cellular and molecular characteristics of the functional IVD. Hence, the phenotype of IVD cells has been of significant interest from multiple perspectives, including development, growth, remodelling, degeneration and repair. One major challenge that complicates our understanding of the disc cells is that both the cellular phenotype and the extracellular matrix strongly depend on disc maturity and health and as a consequence are continuously evolving. This review delineates the diversity of the cell types found in the intervertebral disc, with emphasis on human, but with reference to other species. The cells of the NP appear rounded and express a proteoglycan-rich matrix, whereas the more elongated AF cells are embedded in a collagen fibre matrix and the CEPs represent a layer of cartilage. Even though all disc cells have often been referred to as 'intervertebral disc chondrocytes', distinct phenotypical differences in comparison with articular chondrocytes exist and have been reported recently. The availability of more specific markers has also improved our understanding of progenitor cell differentiation towards an IVD cell phenotype. Ultimately, new cell- and tissue-engineering approaches to regenerative therapies will only be successful if the specific characteristics of the individual tissues and their context in the function of the whole organ, are taken into consideration. PMID: 22686699 [PubMed - indexed for MEDLINE]
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Related Articles [Promotion effect of notochordal cells conditioned medium on proliferation and differentiation of bone marrow mesenchymal stem cells]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2012 May;26(5):601-6 Authors: Ma K, Shao Z, Wang B, Zhang Y, Yang S, Liu T Abstract OBJECTIVE: To investigate the effect of notochordal cells (NCs) conditioned medium (NCCM) on the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). METHODS: NCs and BMSCs were isolated from the thoracolumbar intervertebral disc and the femurs of 4-week-old Japanese white rabbits, respectively. NCs were cultured with DMEM/F12 medium containing 15% FBS for 5 days to prepare NCCM. The experiment consisted of 2 groups: BMSCs were cultured with NCCM in experimental group and with DMEM/F12 medium containing 15% FBS in control group. The proliferation of BMSCs was assessed by cell counting kit-8 at 1, 3, 5, 7, 9, and 14 days after culture; the expression of proteoglycan and collagen type II were determined by immunofluorescence and real-time fluorescent quantitative PCR at 7 and 14 days after culture. RESULTS: NCs and BMSCs were successfully isloated. At 5, 7, 9, and 14 days, the number of BMSCs in the experimental group was significantly more than those in the control group (P < 0.05). At 7 and 14 days, there was no expression or less expression of proteoglycan and collagen type II in the control group; however, there was a lot of expression of proteoglycan and collagen type II in the experimental group, and the expressions were higher at 14 days than at 7 days. At 7 and 14 days after culture, the mRNA expressions of proteoglycan and collagen type II were significantly higher in the experimental group than in the control group (P < 0.05), and at 14 days than at 7 days in the experimental group (P < 0.05). CONCLUSION: NCCM can promote the proliferation and the differentiation of BMSCs into chondroyte-like cells, which provides the basis for NCs and BMSCs as seed cells in the treatment of degenerative disc disease. PMID: 22702058 [PubMed - indexed for MEDLINE]
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Related Articles [Cell therapy in treating age-related intervertebral disc pathology]. Adv Gerontol. 2012;25(1):105-11 Authors: Anisimov SV Abstract Pathology of the spine significantly affects the quality of life and is associated with a high rate of disability. Prevalence of the pathology of the spine increases with advanced age. It may have various causes and is associated with a wide spectrum of significant and variable symptoms. Low back pain (back pain) is the most common syndrome. It is mostly caused by the degeneration of the intervertebral discs, associated with unspecific and irreversible structural alterations in the latter. Surgical treatment of degenerative disc disease (DDD) is symptomatic, thus requiring a development of alternative approaches. In the current review, the principles of regenerative cellular therapy and cell replacement therapy of DDD are analyzed. Various cell types utilized as cellular therapy substrates are compared. PMID: 22708454 [PubMed - indexed for MEDLINE]
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Related Articles New treatments and imaging strategies in degenerative disease of the intervertebral disks. Radiology. 2012 Jul;264(1):6-19 Authors: Lotz JC, Haughton V, Boden SD, An HS, Kang JD, Masuda K, Freemont A, Berven S, Sengupta DK, Tanenbaum L, Maurer P, Ranganathan A, Alavi A, Marinelli NL Abstract Magnetic resonance (MR) imaging in patients with persistent low back pain and sciatica effectively demonstrates spine anatomy and the relationship of nerve roots and intervertebral disks. Except in cases with nerve root compression, disk extrusion, or central stenosis, conventional anatomic MR images do not help distinguish effectively between painful and nonpainful degenerating disks. Hypoxia, inflammation, innervation, accelerated catabolism, and reduced water and glycosaminoglycan content characterize degenerated disks, the extent of which may distinguish nonpainful from painful ones. Applied to the spine, "functional" imaging techniques such as MR spectroscopy, T1ρ calculation, T2 relaxation time measurement, diffusion quantitative imaging, and radio nucleotide imaging provide measurements of some of these degenerative features. Novel minimally invasive therapies, with injected growth factors or genetic materials, target these processes in the disk and effectively reverse degeneration in controlled laboratory conditions. Functional imaging has applications in clinical trials to evaluate the efficacy of these therapies and eventually to select patients for treatment. This report summarizes the biochemical processes in disk degeneration, the application of advanced disk imaging techniques, and the novel biologic therapies that presently have the most clinical promise. PMID: 22723559 [PubMed - indexed for MEDLINE]
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Related Articles Epidural abscess and cauda equina syndrome after percutaneous intradiscal therapy in degenerative lumbar disc disease. Spine J. 2012 Nov;12(11):e1-4 Authors: Subach BR, Copay AG, Martin MM, Schuler TC, DeWolfe DS Abstract BACKGROUND CONTEXT: Percutaneous intradiscal therapies are gaining popularity as a regenerative treatment option for spinal disc degeneration. The risks, benefits, and possible complications associated with such procedures have been poorly defined. As these procedures are performed with increasing frequency, the likelihood that clinicians will be faced with significant complications also increases. PURPOSE: The purpose of this study is to describe a significant complication of a percutaneous intradiscal bone marrow and adipose tissue transplantation for symptomatic lumbar disc degeneration. STUDY DESIGN: The study design is a case report. METHODS: Two weeks after an injection of adipose cells, bone marrow aspirate and plasma into his L3-L4 and L5-S1 lumbar discs, a 64-year-old patient presented to the emergency room with cauda equina syndrome, fever, and back pain. Magnetic resonance imaging diagnosed L3-L4 disc extrusion, discitis with osteomyelitis, and epidural abscess, resulting in emergency decompressive surgery. An epidural abscess was drained, extruded disc material was removed, and cultures obtained. Five days later, once afebrile on antibiotics, he underwent a definitive interbody arthrodesis and stabilization. RESULTS: Cauda equina syndrome resolved, osteomyelitis (methicillin-resistant Staphylococcus epidermidis) was treated, and instrumented arthrodesis stabilized the involved segment. CONCLUSIONS: Complications associated with the intradiscal injection of agents, such as stem cells, fibrin glue, adipose tissue, or bone marrow, have been poorly defined. Given the nature of the degenerating disc, serious adverse events, including discitis, osteomyelitis, and extrusion of disc contents, may occur. PMID: 23131581 [PubMed - indexed for MEDLINE]
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Related Articles The role of Osteocel Plus as a fusion substrate in minimally invasive instrumented transforaminal lumbar interbody fusion. Clin Neurol Neurosurg. 2013 Jul;115(7):991-4 Authors: Ammerman JM, Libricz J, Ammerman MD Abstract BACKGROUND: Instrumented lumbar fusion has become an accepted and effective surgical technique used to address a wide variety of conditions of the lumbar spine. Iliac crest autograft remains the gold standard with regards to bony fusion substrate. Unfortunately there are significant potential disadvantages associated with autograft harvest, including pain, infection, iatrogenic fracture and bleeding. Osteocel Plus (OC+) is an allograft cellular bone matrix containing mesenchymal stem cells (MSCs) and osteoprogenitor cells combined with DBM and cancellous bone. OC+ is designed to mimic the osteobiologic profile of human autograft bone, thereby eliminating the risks of autograft harvest. METHODS: A retrospective chart review was conducted to identify all patients who had undergone a MITLIF with OC+ for degenerative lumbar conditions. Patient demographics including age, sex, history of risk factors for nonunion including: osteoporosis documented on DEXA scanning, diabetes mellitus, smoking or steroid use were examined and recorded. Successful arthrodesis was judged based on post-operative X-ray imaging. RESULTS: 23 patients at 26 spinal levels underwent a MITLIF with OC+. Twenty-one patients (91.3%) and 24 levels (92.3%) went on to achieve radiographic evidence of solid bony arthrodesis by 12 months post-op. Six patients (26%) demonstrated clear evidence of early interbody bone growth within 6 months of surgery. CONCLUSION: OC+ results in robust and reproducible lumbar interbody fusion, in both young and older patients. PMID: 23182179 [PubMed - indexed for MEDLINE]
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Related Articles Clinico-biomechanical issues and dynamic stabilization when considering stem cell treatment for degenerative disc disease. Transplantation. 2013 Jan 27;95(2):e1 Authors: Clemente JM, Clemente JV PMID: 23325008 [PubMed - indexed for MEDLINE]
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Related Articles The effects of microenvironment in mesenchymal stem cell-based regeneration of intervertebral disc. Spine J. 2013 Mar;13(3):352-62 Authors: Huang YC, Leung VY, Lu WW, Luk KD Abstract BACKGROUND CONTEXT: Recent studies have demonstrated new therapeutic strategy using transplantation of mesenchymal stem cells (MSCs), especially bone marrow-derived MSCs (BM-MSCs), to preserve intervertebral disc (IVD) structure and functions. It is important to understand whether and how the MSCs survive and thrive in the hostile microenvironment of the degenerated IVD. Therefore, this review majorly examines how resident disc cells, hypoxia, low nutrition, acidic pH, mechanical loading, endogenous proteinases, and cytokines regulate the behavior of the exogenous MSCs. PURPOSE: To review and summarize the effect of the microenvironment in biological characteristics of BM-MSCs for IVD regeneration; the presence of endogenous stem cells and the state of the art in the use of BM-MSCs to regenerate the IVD in vivo were also discussed. STUDY DESIGN: Literature review. METHODS: MEDLINE electronic database was used to search for articles concerning stem/progenitor cell isolation from the IVD, regulation of the components of microenvironment for MSCs, and MSC-based therapy for IVD degeneration. The search was limited to English language. RESULTS: Stem cells are probably resident in the disc, but exogenous stem cells, especially BM-MSCs, are currently the most popular graft cells for IVD regeneration. The endogenous disc cells and the biochemical and biophysical components in the degenerating disc present a complicated microenvironment to regulate the transplanted BM-MSCs. Although MSCs regenerate the mildly degenerative disc effectively in the experimental and clinical trials, many underlying questions are in need of further investigation. CONCLUSIONS: There has been a dramatic improvement in the understanding of potential MSC-based therapy for IVD regeneration. The use of MSCs for IVD degeneration is still at the stage of preclinical and Phase 1 studies. The effects of the disc microenvironment in MSCs survival and function should be closely studied for transferring MSC transplantation from bench to bedside successfully. PMID: 23340343 [PubMed - indexed for MEDLINE]
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Related Articles Novel cartilage-derived biomimetic scaffold for human nucleus pulposus regeneration: a promising therapeutic strategy for symptomatic degenerative disc diseases. Orthop Surg. 2013 Feb;5(1):60-3 Authors: Yang Q, Zhao YH, Xia Q, Xu BS, Ma XL, Liu Y, Hu YC, Li HF, Miao J, Wang T, Ma JX, Sun XL Abstract Because current therapies have not always been successful and effective, the possibility of regenerating the nucleus pulposus (NP) through a tissue-engineered construct offers a novel therapeutic possibility for symptomatic degenerative disc diseases (DDDs). However, more research is necessary to identify the optimal scaffold, cell type and mixture of signal factors needed for NP regeneration. Numerous possible scaffolds for NP regeneration have been investigated; they have many shortcomings in common. Various biological scaffolds derived from decellularized tissue and organs have been successfully used in tissue engineering and received approval for use in humans. Regretfully, harvesting of human NP is difficult and only small amounts can be obtained. The macromolecules of cartilage, which include collagen and proteoglycan aggrecan, are similar to those of the extracellular matrix of immature NP. Recent studies have shown that adipose-derived stem cells (ADSC) can be induced to develop NP-like phenotypes when stimulated by appropriate signals. We thus reasonably postulated that an ideal NP scaffold for tissue engineering could be fabricated from decellularized cartilage matrix (DCM). Furthermore, a combination of ADSCs and DCM-derived biomimetic scaffolds would be advantageous in NP tissue engineering and, in the long run, could become an effective treatment option for symptomatic DDD. PMID: 23420750 [PubMed - indexed for MEDLINE]
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Related Articles An overview of underlying causes and animal models for the study of age-related degenerative disorders of the spine and synovial joints. J Orthop Res. 2013 Jun;31(6):831-7 Authors: Vo N, Niedernhofer LJ, Nasto LA, Jacobs L, Robbins PD, Kang J, Evans CH Abstract As human lifespan increases so does the incidence of age-associated degenerative joint diseases, resulting in significant negative socioeconomic consequences. Osteoarthritis (OA) and intervertebral disc degeneration (IDD) are the most common underlying causes of joint-related chronic disability and debilitating pain in the elderly. Current treatment methods are generally not effective and involve either symptomatic relief with non-steroidal anti-inflammatory drugs and physical therapy or surgery when conservative treatments fail. The limitation in treatment options is due to our incomplete knowledge of the molecular mechanism of degeneration of articular cartilage and disc tissue. Basic understanding of the age-related changes in joint tissue is thus needed to combat the adverse effects of aging on joint health. Aging is caused at least in part by time-dependent accumulation of damaged organelles and macromolecules, leading to cell death and senescence and the eventual loss of multipotent stem cells and tissue regenerative capacity. Studies over the past decades have uncovered a number of important molecular and cellular changes in joint tissues with age. However, the precise causes of damage, cellular targets of damage, and cellular responses to damage remain poorly understood. The objectives of this review are to provide an overview of the current knowledge about the sources of endogenous and exogenous damaging agents and how they contribute to age-dependent degenerative joint disease, and highlight animal models of accelerated aging that could potentially be useful for identifying causes of and therapies for degenerative joint diseases. PMID: 23483579 [PubMed - indexed for MEDLINE]
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Related Articles Intervertebral disc regeneration: from the degenerative cascade to molecular therapy and tissue engineering. J Tissue Eng Regen Med. 2013 Mar 20; Authors: Vadalà G, Russo F, Di Martino A, Denaro V Abstract Low back pain is one of the major health problems in industrialized countries, as a leading source of disability in the working population. Intervertebral disc degeneration has been identified as its main cause, being a progressive process mainly characterized by alteration of extracellular matrix composition and water content. Many factors are involved in the degenerative cascade, such as anabolism/catabolism imbalance, reduction of nutrition supply and progressive cell loss. Currently available treatments are symptomatic, and surgical procedures consisting of disc removal are often necessary. Recent advances in our understanding of intervertebral disc biology led to an increased interest in the development of novel biological treatments aimed at disc regeneration. Growth factors, gene therapy, stem cell transplantation and biomaterials-based tissue engineering might support intervertebral disc regeneration by overcoming the limitation of the self-renewal mechanism. The aim of this paper is to overview the literature discussing the current status of our knowledge from the degenerative cascade of the intervertebral disc to the latest molecular, cell-based therapies and tissue-engineering strategies for disc regeneration. Copyright © 2013 John Wiley & Sons, Ltd. PMID: 23512973 [PubMed - as supplied by publisher]
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Related Articles [Regeneration strategies of intervertebral disc]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2013 Feb;27(2):227-32 Authors: Fu W, Xiang Z Abstract OBJECTIVE: To review the research progress of the seed cells, scaffolds, growth factors, and the prospects for clinical application of the intervertebral disc regeneration. METHODS: The recent literature concerning the regeneration strategies and tissue engineering for treatment of degenerative intervertebral disc disease was extensively reviewed and summarized. RESULTS: Seed cells based on mesenchymal stem cells (MSCs) and multiple-designed biomimetic scaffolds are the hot topic in the field of intervertebral disc regeneration. It needs to be further investigated how to effectively combine the interactions of seed cells, scaffolds, and growth factors and to play their regulation function. CONCLUSION: The biological regeneration of intervertebral disc would have a very broad prospects for clinical application in future. PMID: 23596694 [PubMed - indexed for MEDLINE]
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Related Articles Molecular and genetic advances in the regeneration of the intervertebral disc. Surg Neurol Int. 2013;4(Suppl 2):S94-S105 Authors: Maerz T, Herkowitz H, Baker K Abstract BACKGROUND: Owing to the debilitating nature of degenerative disc disease (DDD) and other spine pathologies, significant research has been performed with the goal of healing or regenerating the intervertebral disc (IVD). Structural complexity, coupled with low vascularity and cellularity, make IVD regeneration an extremely challenging task. METHODS: Tissue engineering-based strategies utilize three components to enhance tissue regeneration; scaffold materials to guide cell growth, biomolecules to enhance cell migration and differentiation, and cells (autologous, or allogeneic) to initiate the process of tissue formation. Significant advances in IVD regeneration have been made utilizing these tissue engineering strategies. RESULTS: The current literature demonstrates that members of the transforming growth factor beta (TGF-β) superfamily are efficacious in the regeneration of an anabolic response in the IVD and to facilitate chondrogenic differentiation. Gene therapy, though thwarted by safety concerns and the risk of ectopic transfection, has significant potential for a targeted and sustained regenerative response. Stem cells in combination with injectable, biocompatible, and biodegradable scaffolds in the form of hydrogels can differentiate into de novo IVD tissue and facilitate regeneration of the existing matrix. Therapies that address both anabolism and the inherent catabolic state of the IVD using either direct inhibitors or broad-spectrum inhibitors show extensive promise. CONCLUSION: This review article summarizes the genetic and molecular advances that promise to play an integral role in the development of new strategies to combat DDD and promote healing of injured discs. PMID: 23646279 [PubMed]
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Related Articles Assessment of the matrix degenerative effects of MMP-3, ADAMTS-4, and HTRA1, injected into a bovine intervertebral disc organ culture model. Spine (Phila Pa 1976). 2013 Oct 15;38(22):E1377-87 Authors: Furtwängler T, Chan SC, Bahrenberg G, Richards PJ, Gantenbein-Ritter B Abstract STUDY DESIGN: In vitro study to develop an intervertebral disc degeneration organ culture model, using coccygeal bovine intervertebral discs (IVDs) and injection of proteolytic enzymes MMP-3, ADAMTS-4, and HTRA1. OBJECTIVE: This study aimed to develop an in vitro model of enzyme-mediated intervertebral disc degeneration to mimic the clinical outcome in humans for investigation of therapeutic treatment options. SUMMARY OF BACKGROUND DATA: Bovine IVDs are comparable with human IVDs in terms of cell composition and biomechanical behavior. Researchers injected papain and trypsin into them to create an intervertebral disc degeneration model with a degenerated nucleus pulposus (NP) area. They achieved macroscopic cavities as well as a loss of glycosaminoglycans (GAGs). However, none of these enzymes are clinically relevant. METHODS: Bovine IVDs were harvested maintaining the endplates. Active forms of MMP-3, ADAMTS-4, and HTRA1 were injected at a dose of 10 μg/mL each. Phosphate-buffered saline was injected as a control. Discs were cultured for 8 days and loaded diurnally (days 1-4 with ≈0.4 MPa for 16 hr) and left under free swelling condition from days 4 to 8 to avoid expected artifacts because of dehydration of the NP. Outcome parameters included disc height, metabolic cell activity, DNA content, GAG content, total collagen content, relative gene expression, and histological investigation. RESULTS: The mean metabolic cell activity was significantly lower in the NP area of discs injected with ADAMTS-4 than the day 0 control discs. Disc height was decreased after injection with HTRA1 and was significantly correlated with changes in GAG/DNA of the NP tissue. Total collagen content tended to be lower in groups injected with ADAMTS4 and MMP-3. CONCLUSION: MMP-3, ADAMTS-4, and HTRA1 provoked neither visible matrix degradation nor major shifts in gene expression. However, cell activity was significantly reduced and HTRA1 induced loss of disc height that positively correlated with changes in GAG/DNA content. The use of higher doses of these enzymes or a combination thereof may, therefore, be necessary to induce disc degeneration. PMID: 23778376 [PubMed - in process]
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Related Articles Analysis of molecular expression in adipose tissue-derived mesenchymal stem cells : prospects for use in the treatment of intervertebral disc degeneration. J Korean Neurosurg Soc. 2013 Apr;53(4):207-12 Authors: Jin ES, Min J, Jeon SR, Choi KH, Jeong JH Abstract OBJECTIVE: Recent studies have shown encouraging progress toward the use of autogenic and allogenic mesenchymal stem cells (MSCs) to arrest, or even lead to partial regeneration in, intervertebral disc (IVD) degeneration. However, this technology is still in its infancy, and further development is required. The aim of this study was to analyze whether rat adipose-derived mesenchymal stem cells (ADMSC) can differentiate towards IVD-like cells after treatment with transforming growth factor β3 (TGF-β3) in vitro. We also performed quantitative analysis of gene expression for ADMSC only, ADMSCs treated with TGF-β3, and co-cultured ADMSCs treated with TGF-β3. METHODS: ADMSCs were sub-cultured to homogeneity and used in fluorocytometry assays for CD11, CD45, and CD90/Thy1. ADMSCs were differentiated in spheroid culture towards the chondrogenic lineage by the presence of TGF-β3, dexamethasone, and ascorbate. We also co-cultured pure ADMSCs and nucleus pulposus cells in 24-well plates, and performed immunohistochemical staining, western blotting, and RT-PCR for quantitativeanalysis of gene expression. RESULTS: Results of fluorocytometry were positive for CD90/Thy1 and negative for CD11 and CD45. TGF-β3-mediated induction of ADMSCs led to the expression of the differentiation markers of intervertebral disc-like cells, such as aggrecan, collagen II, and sox-9. Co-cultured ADMSCs treated with TGF-β3 showed higher expression of differentiation markers and greater extracellular matrix production compared with ADMSCs treated with TGF-β3 alone. CONCLUSION: ADMSC treated with TGF-β3 may be an attractive source for regeneration therapy in degenerative IVD. These findings may also help elucidate the pathologic mechanism of MSC therapy in the degeneration of IVD in vivo. PMID: 23826475 [PubMed]
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Related Articles [Research situation of stem cells transplantation for intervertebral disc degeneration]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2013 May;27(5):575-9 Authors: Wang F, Wu X, Wang Y, Bao J Abstract OBJECTIVE: To summarize the research situation of stem cells transplantation for intervertebral disc (IVD) degeneration.degeneration. METHODS: The original articles about stem cells transplantation for repair of IVD degeneration were extensively reviewed; the clinical applications, the mechanisms, and related factors to influence repair effect were analyzed; and obstaclesreviewed; the clinical applications, the mechanisms, and related factors to influence repair effect were analyzed; and obstacles RESULTS: Autogenic stem cells transplantation can repair IVD degeneration and effectively relieve the symptoms of low back and leg pain. Stem cells can differentiate into disc chondrocytes in the disc microenvironment, increase the production of various growth factors, and exert a trophic effect on disc cells. It is also evident that the transplanted stem cells can potentially protect disc cells from apoptosis and maintain an immune-privileged state in the IVD. Multiple factors such as tissue origin of stem cells, methods to pre-modulate the seeds, choice of injectable scaffolds, and even the severity of degeneration are closely related to the repair effects. To get a more efficient stem cell therapy, future researches are challenged to modulate the migration and distribution of stem cells in the IVD, avoid flow back, and better understand their ability to restore stemnness properties within the degenerative disc niche. CONCLUSION: Stem cells transplantation is proven to be a promising biological approach for repair of IVD degeneration. PMID: 23879095 [PubMed - indexed for MEDLINE]
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Related Articles Effect of cryopreservation on canine and human activated nucleus pulposus cells: a feasibility study for cell therapy of the intervertebral disc. Biores Open Access. 2013 Aug;2(4):273-82 Authors: Tanaka M, Sakai D, Hiyama A, Arai F, Nakajima D, Nukaga T, Nakai T, Mochida J Abstract It has been shown that coculture of bone marrow-derived stromal cells (BMSCs) with intervertebral disc (IVD) nucleus pulposus (NP) cells significantly activates the biological characteristics of NP cells in animal models and in humans. We therefore predicted that activated NP cells would be a useful graft source for cellular transplantation therapy in the treatment of degenerative IVDs. However, the activation protocol is based on fresh isolation and activation of NP cells, which limits the timing of clinical application. Cell transplantation therapy could be offered to more patients than is now possible if activated NP cells could be transplanted as and when required by the condition of the patient. No study has investigated the effect of cryopreservation on NP cells after enzymatic isolation. We investigated the effects of cryopreservation of canine and human NP cells in both cell and tissue form before coculture with autologous BMSCs. Cell viability, proliferation, glycosaminoglycan production, aggrecan transcriptional activity, colony generation, and gene expression profile of the cells after cryopreservation and subsequent coculture were analyzed. The influence of cryopreservation on cell chromosomal abnormalities and tumorigenesis was also studied. The results showed that there were no clear differences between the noncryopreserved and cryopreserved cells in terms of cell viability, proliferation capacity, and capacity to synthesize extracellular matrix. Furthermore, the cells showed no apparent chromosomal abnormalities or tumorigenic ability and exhibited similar patterns of gene expression. These findings suggest that by using cryopreservation, it may be possible to transplant activated NP cells upon request for patients' needs. PMID: 23914334 [PubMed]
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Related Articles Stemming the Degeneration: IVD Stem Cells and Stem Cell Regenerative Therapy for Degenerative Disc Disease. Adv Stem Cells. 2013;2013 Authors: Sivakamasundari V, Lufkin T Abstract The intervertebral disc (IVD) is immensely important for the integrity of vertebral column function. The highly specialized IVD functions to confer flexibility and tensile strength to the spine and endures various types of biomechanical force. Degenerative disc disease (DDD) is a prevalent musculoskeletal disorder and is the major cause of low back pain and includes the more severe degenerative lumbar scoliosis, disc herniation and spinal stenosis. DDD is a multifactorial disorder whereby an imbalance of anabolic and catabolic factors, or alterations to cellular composition, or biophysical stimuli and genetic background can all play a role in its genesis. However, our comprehension of IVD formation and theetiology of disc degeneration (DD) are far from being complete, hampering efforts to formulate appropriate therapies to tackle DD. Knowledge of the stem cells and various techniques to manipulate and direct them to particular fates have been promising in adopting a stem-cell based regenerative approach to DD. Moreover, new evidence on the residence of stem/progenitor cells within particular IVD niches has emerged holding promise for future therapeutic applications. Existing issues pertaining to current therapeutic approaches are also covered in this review. PMID: 23951558 [PubMed - as supplied by publisher]
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Related Articles Dual release of dexamethasone and TGF-β3 from polymeric microspheres for stem cell matrix accumulation in a rat disc degeneration model. Acta Biomater. 2013 Dec;9(12):9423-33 Authors: Liang CZ, Li H, Tao YQ, Peng LH, Gao JQ, Wu JJ, Li FC, Hua JM, Chen QX Abstract Low back pain is frequently caused by nucleus pulposus (NP) degeneration. Tissue engineering is a powerful therapeutic strategy which could restore the normal biomechanical motion of the human spine. Previously we reported that a new nanostructured three-dimensional poly(lactide-co-glycolide) (PLGA) microsphere, which is loaded with dexamethasone and growth factor embedded heparin/poly(l-lysine) nanoparticles via a layer-by-layer system, was an effective cell carrier in vitro for NP tissue engineering. This study aimed to investigate whether the implantation of adipose-derived stem cell (ADSC)-seeded PLGA microspheres into the rat intervertebral disc could regenerate the degenerated disc. Changes in disc height by plain radiograph, T2-weighted signal intensity in magnetic resonance imaging (MRI), histology, immunohistochemistry and matrix-associated gene expression were evaluated in normal controls (NCs) (without operations), a degeneration control (DC) group (with needle puncture, injected only with Dulbecco's modified Eagle's medium), a PLGA microspheres (PMs) treatment group (with needle puncture, PLGA microspheres only injection), and PLGA microspheres loaded with ADSCs treatment (PMA) group (with needle puncture, PLGA microspheres loaded with ADSC injection) for a 24-week period. The results showed that at 24 weeks post-transplantation, the PM and PMA groups regained disc height values of ∼63% and 76% and MRI signal intensities of ∼47% and 76%, respectively, compared to the NC group. Biochemistry, immunohistochemistry and gene expression analysis also indicated the restoration of proteoglycan accumulation in the discs of the PM and PMA groups. However, there was almost no restoration of proteoglycan accumulation in the discs of the DC group compared with the PM and PMA groups. Taken together, these data suggest that ADSC-seeded PLGA microspheres could partly regenerate the degenerated disc in vivo after implantation into the rat degenerative intervertebral disc. PMID: 23973308 [PubMed - in process]
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Related Articles An injectable hydrogel incorporating mesenchymal precursor cells and pentosan polysulphate for intervertebral disc regeneration. Biomaterials. 2013 Dec;34(37):9430-40 Authors: Frith JE, Cameron AR, Menzies DJ, Ghosh P, Whitehead DL, Gronthos S, Zannettino AC, Cooper-White JJ Abstract Intervertebral disc (IVD) degeneration is one of the leading causes of lower back pain and a major health problem worldwide. Current surgical treatments include excision or immobilisation, with neither approach resulting in the repair of the degenerative disc. As such, a tissue engineering-based approach in which stem cells, coupled with an advanced delivery system, could overcome this deficiency and lead to a therapy that encourages functional fibrocartilage generation in the IVD. In this study, we have developed an injectable hydrogel system based on enzymatically-crosslinked polyethylene glycol and hyaluronic acid. We examined the effects of adding pentosan polysulphate (PPS), a synthetic glycosaminoglycan-like factor that has previously been shown (in vitro and in vivo) to this gel system in order to induce chondrogenesis in mesenchymal precursor cells (MPCs) when added as a soluble factor, even in the absence of additional growth factors such as TGF-β. We show that both the gelation rate and mechanical strength of the resulting hydrogels can be tuned in order to optimise the conditions required to produce gels with the desired combination of properties for an IVD scaffold. Human immunoselected STRO-1+ MPCs were then incorporated into the hydrogels. They were shown to retain good viability after both the initial formation of the gel and for longer-term culture periods in vitro. Furthermore, MPC/hydrogel composites formed cartilage-like tissue which was significantly enhanced by the incorporation of PPS into the hydrogels, particularly with respect to the deposition of type-II-collagen. Finally, using a wild-type rat subcutaneous implantation model, we examined the extent of any immune reaction and confirmed that this matrix is well tolerated by the host. Together these data provide evidence that such a system has significant potential as both a delivery vehicle for MPCs and as a matrix for fibrocartilage tissue engineering applications. PMID: 24050877 [PubMed - in process]
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Related Articles Stem cells in preclinical spine studies. Spine J. 2013 Nov 15; Authors: Werner BC, Li X, Shen FH Abstract BACKGROUND CONTEXT: The recent identification and characterization of mesenchymal stem cells have introduced a shift in the research focus for future technologies in spinal surgery to achieve spinal fusion and treat degenerative disc disease. Current and past techniques use allograft to replace diseased tissue or rely on host responses to recruit necessary cellular progenitors. Adult stem cells display long-term proliferation, efficient self-renewal, and multipotent differentiation. PURPOSE: This review will focus on two important applications of stem cells in spinal surgery: spine fusion and the management of degenerative disc disease. STUDY DESIGN: Review of the literature. METHODS: Relevant preclinical literature regarding stem cell sources, growth factors, scaffolds, and animal models for both osteogenesis and chondrogenesis will be reviewed, with an emphasis on those studies that focus on spine applications of these technologies. RESULTS: In both osteogenesis and chondrogenesis, adult stem cells derived from bone marrow or adipose show promise in preclinical studies. Various growth factors and scaffolds have also been shown to enhance the properties and eventual clinical potential of these cells. Although its utility in clinical applications has yet to be proven, gene therapy has also been shown to hold promise in preclinical studies. CONCLUSIONS: The future of spine surgery is constantly evolving, and the recent advancements in stem cell-based technologies for both spine fusion and the treatment of degenerative disc disease is promising and indicative that stem cells will undoubtedly play a major role clinically. It is likely that these stem cells, growth factors, and scaffolds will play a critical role in the future for replacing diseased tissue in disease processes such as degenerative disc disease and in enhancing host tissue to achieve more reliable spine fusion. PMID: 24246748 [PubMed - as supplied by publisher]
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Related Articles Cell sources for nucleus pulposus regeneration. Eur Spine J. 2013 Dec 3; Authors: Kregar Velikonja N, Urban J, Fröhlich M, Neidlinger-Wilke C, Kletsas D, Potocar U, Turner S, Roberts S Abstract PURPOSE: There is increasing interest in the development of cell therapy as a possible approach for the treatment of degenerative disc disease. To regenerate nucleus pulposus tissue, the cells must produce an appropriate proteoglycan-rich matrix, as this is essential for the functioning of the intervertebral disc. The natural environment within the disc is very challenging to implanted cells, particularly if they have been subcultured in normal laboratory conditions. The purpose of this work is to discuss parameters relevant to translating different proposed cell therapies of IVD into clinical use. RESULTS: Several sources of cells have been proposed, including nucleus pulposus cells, chondrocytes and mesenchymal stem cells derived from bone marrow or adipose tissue. There are some clinical trials and reports of attempts to regenerate nucleus pulposus utilising either autologous or allogenic cells. While the published results of clinical applications of these cell therapies do not indicate any safety issues, additional evidence will be needed to prove their long-term efficacy. CONCLUSION: This article discusses parameters relevant for successful translation of research on different cell sources into clinically applicable cell therapies: the influence of the intervertebral disc microenvironment on the cell phenotype, issues associated with cell culture and technical preparation of cell products, as well as discussing current regulatory requirements. There are advantages and disadvantages of each proposed cell type, but no strong evidence to favour any one particular cell source at the moment. PMID: 24297331 [PubMed - as supplied by publisher]
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