Multiple Sclerosis Stem Cell Treatment

Multiple Sclerosis and Stem Cell Therapy

What is MS?

Multiple Sclerosis and Stem Cell Treatment

Multiple Sclerosis and Stem Cell Therapy

Multiple sclerosis is also known as disseminated sclerosis or encephalomyelitis disseminata.

It is an inflammatory disease where the fatty myelin sheaths around the axons of the brain and spinal cord are damaged. The disease often leads to demyelination and scarring.

The disease usually appears in young adults and is more common in women. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other.

Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin.

In MS, the body's own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals.

The name multiple sclerosis refers to scars (scleroses—better known as plaques or lesions) particularly in the white matter of the brain and spinal cord, which is mainly composed of myelin.

Although much is known about the mechanisms involved in the disease process, the cause remains unknown. There is currently no known cure for multiple sclerosis and treatments attempt to return function after an attack, prevent new attacks, and prevent disability.

 

Multiple Sclerosis and Stem Cell Therapy

Immune Reconstitution after Double Umbilical Cord Blood Stem Cell Transplantation: Comparison with Unrelated Peripheral Blood Stem Cell Transplantation.


2011 Aug 26. [Epub ahead of print]

Jacobson CA, Turki AT, McDonough SM, Stevenson KE, Kim HT, Kao G, Herrera MI, Reynolds CG, Alyea EP, Ho VT, Koreth J, Armand P, Chen YB, Ballen K, Soiffer RJ, Antin JH, Cutler CS, Ritz J.


Source Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.


Abstract
Double umbilical cord blood (DUCB) transplantation is an accepted transplantation strategy for patients without suitable human leukocyte antigen (HLA) matched donors. However, DUCB transplantation is associated with increased morbidity and mortality because of slow recovery of immunity and a high risk of infection. To define the differences in immune reconstitution between DUCB transplantation and HLA matched unrelated donor (MUD) transplantation, we performed a detailed, prospective analysis of immune reconstitution in 42 DUCB recipients and 102 filgrastim-mobilized unrelated peripheral blood stem cell recipients.

Reconstitution of CD3 T cells was significantly delayed in the DUCB cohort compared with the MUD cohort for 1 to 6 months posttransplantation (P < .001), including naive (CD45RO-) and memory (CD45RO+) CD4 T cells, regulatory (CD4CD25) T cells, and CD8 T cells. In contrast, CD19 B cells recovered more rapidly in the DUCB cohort and numbers remained significantly greater from 3 to 24 months after transplantation (P = .001).

CD56CD16 natural killer (NK) cells also recovered more rapidly in DUCB recipients and remained significantly greater from 1 to 24 months after transplantation. B cell activating factor (BAFF) levels were higher in the DUCB cohort at 1 month (P < .001), were similar in both cohorts at 3 and 6 months, and were lower in the DUCB cohort at 12 months (P = .002). BAFF/CD19 B cell ratios were lower in the DUCB cohort at 3 (P = .045), 6 (P = .02), and 12 months (P = .002) after transplantation. DUCB recipients had more infections within the first 100 days after transplantation (P < .001), and there was less chronic graft-versus-host disease (P < .001), but there were no differences in cumulative incidence of relapse, nonrelapse death, progression-free survival, or overall survival between the 2 groups. These results suggest that increased risk of infections is specifically associated with delayed reconstitution of all major T cell subsets, but the increased risk is limited to the first 3 months after DUCB transplantation. There is no increased risk of relapse, suggesting that graft-versus-leukemia activity is maintained. Early reconstitution of B cells and NK cells may, in part, account for these findings.


PMID: 21875503 [PubMed - as supplied by publisher]

 

Adult stem cells and multiple sclerosis.

Cell Prolif. 2011 Apr;44 Suppl 1:35-8

Authors: Scolding N

Multiple sclerosis (MS) is a common neurological disease and a major cause of disability, particularly affecting young adults.

It is characterized by patches of damage occurring throughout the brain and spinal cord, with loss of myelin sheaths - the insulating material around nerve fibres that allows normal conduction of nerve impulses - accompanied by loss of cells that make myelin (oligodendrocytes).

 

In addition, we now know that there is damage to nerve cells (neurones) and their fibres (axons) too, and that this occurs both within these discrete patches and in tissue between them. The cause of MS remains unknown, but an autoimmune reaction against oligodendrocytes and myelin is generally assumed to play a major role, and early acute MS lesions almost invariably show prominent inflammation.

Efforts to develop cell therapy in MS have long been directed towards directly implanting cells capable of replacing lost oligodendrocytes and regenerating myelin sheaths.

Accordingly, the advent of techniques to generate large numbers of oligodendrocytes from embryonic stem cells appeared a significant step towards new stem cell treatments for MS; while the emerging consensus that adult stem cells from, for example, the bone marrow had far less potential to turn into oligodendrocytes was thought to cast doubt on their potential value in this disease.

A number of scientific and medical concerns, not least the risk of tumour formation associated with embryonic stem cells, have however, prevented any possible clinical testing of these cells in patients.

 

More recently, increasing understanding of the complexity of tissue damage in MS has emphasized that successful cell therapy may need to achieve far more than simply offering a source of replacement myelin-forming cells.

The many and varied reparative properties of bone marrow-derived (mesenchymal) stem cells may well offer new and attractive possibilities for developing cell-based treatments for this difficult and disabling condition.

PMID: 21481041 [PubMed - in process]

Related Articles Age of the donor reduces the ability of human adipose-derived stem cells to alleviate symptoms in the experimental autoimmune encephalomyelitis mouse model. Stem Cells Transl Med. 2013 Oct;2(10):797-807 Authors: Scruggs BA, Semon JA, Zhang X, Zhang S, Bowles AC, Pandey AC, Imhof KM, Kalueff AV, Gimble JM, Bunnell BA Abstract There is a significant clinical need for effective therapies for primary progressive multiple sclerosis, which presents later in life (i.e., older than 50 years) and has symptoms that increase in severity without remission. With autologous mesenchymal stem cell therapy now in the early phases of clinical trials for all forms of multiple sclerosis (MS), it is necessary to determine whether autologous stem cells from older donors have therapeutic effectiveness. In this study, the therapeutic efficacy of human adipose-derived mesenchymal stem cells (ASCs) from older donors was directly compared with that of cells from younger donors for disease prevention. Mice were induced with chronic experimental autoimmune encephalomyelitis (EAE) using the myelin oligodendrocyte glycoprotein35-55 peptide and treated before disease onset with ASCs derived from younger (<35 years) or older (>60 years) donors. ASCs from older donors failed to ameliorate the neurodegeneration associated with EAE, and mice treated with older donor cells had increased central nervous system inflammation, demyelination, and splenocyte proliferation in vitro compared with the mice receiving cells from younger donors. Therefore, the results of this study demonstrated that donor age significantly affects the ability of human ASCs to provide neuroprotection, immunomodulation, and/or remyelination in EAE mice. The age-related therapeutic differences corroborate recent findings that biologic aging occurs in stem cells, and the differences are supported by evidence in this study that older ASCs, compared with younger donor cells, secrete less hepatocyte growth factor and other bioactive molecules when stimulated in vitro. These results highlight the need for evaluation of autologous ASCs derived from older patients when used as therapy for MS. PMID: 24018793 [PubMed - indexed for MEDLINE]
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Related Articles Suppression of experimental autoimmune encephalomyelitis by interleukin-10 transduced neural stem/progenitor cells. J Neuroinflammation. 2013;10:117 Authors: Klose J, Schmidt NO, Melms A, Dohi M, Miyazaki J, Bischof F, Greve B Abstract Neural stem/progenitor cells (NSPCs) have the ability to migrate into the central nervous system (CNS) to replace damaged cells. In inflammatory CNS disease, cytokine transduced neural stem cells may be used as vehicles to specifically reduce inflammation and promote cell replacement. In this study, we used NSPCs overexpressing IL-10, an immunomodulatory cytokine, in an animal model for CNS inflammation and multiple sclerosis (MS). Intravenous injection of IL-10 transduced neural stem/progenitor cells (NSPC(IL-10)) suppressed myelin oligodendrocyte glycoprotein aa 35-55 (MOG35-55)- induced experimental autoimmune encephalomyelitis (EAE) and, following intravenous injection, NSPC(IL-10) migrated to peripheral lymphoid organs and into the CNS. NSPC(IL-10 )suppressed antigen-specific proliferation and proinflammatory cytokine production of lymph node cells obtained from MOG35-55 peptide immunized mice. In this model, IL-10 producing NSPCs act via a peripheral immunosuppressive effect to attenuate EAE. PMID: 24053338 [PubMed - indexed for MEDLINE]
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Related Articles An observational study of autologous bone marrow-derived stem cells transplantation in seven patients with nervous system diseases: a 2-year follow-up. Cell Biochem Biophys. 2014 May;69(1):179-87 Authors: Ren C, Geng RL, Ge W, Liu XY, Chen H, Wan MR, Geng DQ Abstract Currently, autologous bone marrow-derived stem cell is one of the most innovative areas of stem cells research. Previous studies on animal models of nervous system diseases have shown that these cells have a good effect on nervous system disorders. The alternative treatment with stem cells for the nervous system diseases has also gradually reached to clinical application stage. The prospect is captivating, but the safety and efficacy of this procedure need further research. To observe the clinical efficacy and side effects of the treatment for autologous mesenchymal stem cells and neural stem/progenitor cells which are in differentiated form by inducing with cerebrospinal fluid in the patients with nervous system diseases, thirty patients were selected from our hospital (2009-10 to 2012-07) and were followed at 1 month, 3 months, 6 months, 1 year and 2 years after the treatment with autologous mesenchymal stem cells and neural stem/progenitor cells in differentiated form was introduced. In this paper, we will introduce the process to make cells accessible for the clinical application by the description of the changes observed in 7 cases were followed for 2 years. The time for bone marrow mesenchymal stem cells could be available for clinical needs is as early as 5 days, not later than 10 days, and the median time is 8 days, while neural stem/progenitor cells in differentiated form can be available for clinical needs in as early as 12 days, not later than 15 days, and the median time is 13.5 days (statistical explanation: Case 5 only uses autologous mesenchymal stem cells, and Case 7 has two times bone marrow punctures). The neurological function of the patients was improved in 1-month follow-up, and the patients have a better discontinuous trend (statistical explanation: sometimes the neurological function of the patients between two adjacent follow-ups does not change significantly). After transplantation, four patients appeared to have transient fever, but it was easily controlled by symptomatic treatment. Seven patients did not appear to show secondary tumor induced by transplantation of stem cells in 2-year follow-up. Thus, it suggests that the use of autologous bone marrow-derived stem cells transplantation in patients with nervous system diseases is a feasible, convenient, safe, and effective method. PMID: 24062130 [PubMed - indexed for MEDLINE]
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Related Articles Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014 Feb;141(2):125-39 Authors: Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, Yao Y Abstract Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases. PMID: 24076269 [PubMed - indexed for MEDLINE]
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Related Articles Cell-based reparative therapies for multiple sclerosis. Curr Neurol Neurosci Rep. 2013 Nov;13(11):397 Authors: Ben-Hur T, Fainstein N, Nishri Y Abstract The strong rationale for cell-based therapy in multiple sclerosis is based on the ability of stem and precursor cells of neural and mesenchymal origin to attenuate neuroinflammation, to facilitate endogenous repair processes, and to participate directly in remyelination, if directed towards a myelin-forming fate. However, there are still major gaps in knowledge regarding induction of repair in chronic multiple sclerosis lesions, and whether transplanted cells can overcome the multiple environmental inhibitory factors which underlie the failure of endogenous repair. Major challenges in clinical translation include the determination of the optimal cellular platform, the route of cell delivery, and candidate patients for treatment. PMID: 24078453 [PubMed - indexed for MEDLINE]
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Related Articles Cell therapy for multiple sclerosis: an evolving concept with implications for other neurodegenerative diseases. Lancet. 2013 Oct 5;382(9899):1204-13 Authors: Rice CM, Kemp K, Wilkins A, Scolding NJ Abstract Multiple sclerosis is a major cause of neurological disability, and particularly occurs in young adults. It is characterised by conspicuous patches of damage throughout the brain and spinal cord, with loss of myelin and myelinating cells (oligodendrocytes), and damage to neurons and axons. Multiple sclerosis is incurable, but stem-cell therapy might offer valuable therapeutic potential. Efforts to develop stem-cell therapies for multiple sclerosis have been conventionally built on the principle of direct implantation of cells to replace oligodendrocytes, and therefore to regenerate myelin. Recent progress in understanding of disease processes in multiple sclerosis include observations that spontaneous myelin repair is far more widespread and successful than was previously believed, that loss of axons and neurons is more closely associated with progressive disability than is myelin loss, and that damage occurs diffusely throughout the CNS in grey and white matter, not just in discrete, isolated patches or lesions. These findings have introduced new and serious challenges that stem-cell therapy needs to overcome; the practical challenges to achieve cell replacement alone are difficult enough, but, to be useful, cell therapy for multiple sclerosis must achieve substantially more than the replacement of lost oligodendrocytes. However, parallel advances in understanding of the reparative properties of stem cells--including their distinct immunomodulatory and neuroprotective properties, interactions with resident or tissue-based stem cells, cell fusion, and neurotrophin elaboration--offer renewed hope for development of cell-based therapies. Additionally, these advances suggest avenues for translation of this approach not only for multiple sclerosis, but also for other common neurological and neurodegenerative diseases. PMID: 24095194 [PubMed - indexed for MEDLINE]
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Related Articles A regenerative approach to the treatment of multiple sclerosis. Nature. 2013 Oct 17;502(7471):327-32 Authors: Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T, Gage FH, Theofilopoulos AN, Lawson BR, Schultz PG, Lairson LL Abstract Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches. PMID: 24107995 [PubMed - indexed for MEDLINE]
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Related Articles Can we switch microglia's phenotype to foster neuroprotection? Focus on multiple sclerosis. Immunology. 2014 Mar;141(3):328-39 Authors: Giunti D, Parodi B, Cordano C, Uccelli A, Kerlero de Rosbo N Abstract Microglia cells, the resident innate immune cells in the brain, are highly active, extending and retracting highly motile processes through which they continuously survey their microenvironment for 'danger signals' and interact dynamically with surrounding cells. Upon sensing changes in their central nervous system microenvironment, microglia become activated, undergoing morphological and functional changes. Microglia activation is not an 'all-or-none' process, but rather a continuum depending on encountered stimuli, which is expressed through a spectrum of molecular and functional phenotypes ranging from so-called 'classically activated', with a highly pro-inflammatory profile, to 'alternatively activated' associated with a beneficial, less inflammatory, neuroprotective profile. Microglia activation has been demonstrated in most neurological diseases of diverse aetiology and has been implicated as a contributor to neurodegeneration. The possibility to promote microglia's neuroprotective phenotype has therefore become a therapeutic goal. We have focused our discussion on the role of microglia in multiple sclerosis, a prototype of inflammatory, demyelinating, neurodegenerative disease, and on the effect of currently approved or on-trial anti-inflammatory therapeutic strategies that might mediate neuroprotection at least in part through their effect on microglia by modifying their behaviour via a switch of their functional phenotype from a detrimental to a protective one. In addition to pharmaceutical approaches, such as treatment with glatiramer acetate, interferon-β, fingolimod or dimethyl fumarate, we address the alternative therapeutic approach of treatment with mesenchymal stem cells and their potential role in neuroprotection through their 'calming' effect on microglia. PMID: 24116890 [PubMed - indexed for MEDLINE]
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Related Articles T cells from autoimmune patients display reduced sensitivity to immunoregulation by mesenchymal stem cells: role of IL-2. Autoimmun Rev. 2014 Feb;13(2):187-96 Authors: Ben-Ami E, Miller A, Berrih-Aknin S Abstract Mesenchymal stem cells (MSCs) are multipotent progenitor cells which have been shown to possess broad immunoregulatory and anti-inflammatory capabilities, making them a promising tool to treat autoimmune diseases (AIDs). Nevertheless, as in recent years T cells from AID patients have been found to resist suppression by regulatory T cells, the question of whether they could be regulated by MSCs arises. To use MSCs as a therapeutic tool in human autoimmune diseases, one prerequisite is that T cells from autoimmune patients will be sensitive to these stem cells. The aim of this work was to investigate the ability of healthy donor derived MSCs to inhibit the proliferation of T cells from two pathophysiologically different AIDs: Multiple Sclerosis (MS) and Myasthenia Gravis (MG). We show that MSC-induced inhibition of interferon-γ production and surface expression of the CD3, CD4 and CD28 receptors by activated lymphocytes was similar in the AID patients and healthy controls. Contrarily, the MSCs' ability to suppress the proliferation of T cells of both diseases was significantly weaker compared to their ability to affect T cells of healthy individuals. Although we found that the inhibitory mechanism is mediated through CD14+ monocytes, the faulty cellular component is the patients' T cells. MSC-treated MS and MG lymphocytes were shown to produce significantly more IL-2 than healthy subjects while coupling of the MSC treatment with neutralizing IL-2 antibodies resulted in inhibition levels similar to those of the healthy controls. MSCs were also found to down-regulate the lymphocyte surface expression of the IL-2 receptor (CD25) through both transcription inhibition and induction of receptor shedding. Addition of IL-2 to MSC-inhibited lymphocytes restored proliferation thus suggesting a key role played by this cytokine in the inhibitory mechanism. Taken together, these results demonstrate the potential of a MSC-based cellular therapy for MS, MG and possibly other autoimmune diseases but also highlight the need for a better understanding of the underlying mechanisms for development and optimization of clinical protocols. PMID: 24121085 [PubMed - indexed for MEDLINE]
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Related Articles Mobilization of progenitors in the subventricular zone to undergo oligodendrogenesis in the Theiler's virus model of multiple sclerosis: implications for remyelination at lesions sites. Exp Neurol. 2013 Dec;250:348-52 Authors: Mecha M, Feliú A, Carrillo-Salinas FJ, Mestre L, Guaza C Abstract Remyelination involves the generation of new myelin sheaths around axons, as occurs spontaneously in many multiple sclerosis (MS) lesions and other demyelinating diseases. When considering repairing a diseased brain, the adult mouse subventricular zone (SVZ) is of particular interest since the stem cells in this area can migrate and differentiate into the three major cell types in the central nervous system (CNS). In Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), we assessed the relative contribution of the SVZ to the remyelination in the corpus callosum at preclinical stages in this MS model. CNPase, MBP and Luxol Fast Blue staining revealed prominent demyelination 35days post-infection (dpi), concomitant with a strong staining in GFAP(+) type B astrocytes in the SVZ and the increased proliferation in this area. The migration of oligodendrocyte progenitors from the SVZ contributed to the remyelination observed at 60 dpi, evident through the number of APC(+)/BrdU(+) mature oligodendrocytes in the corpus callosum of infected animals. These data suggest that the inflammation induced by the Theiler's virus not only provokes strong preclinical demyelination but also, it is correlated with oligodendrocyte generation in the adult SVZ, cells that along with resident progenitor cells contribute to the prompt remyelination observed in the corpus callosum. PMID: 24148569 [PubMed - indexed for MEDLINE]
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Related Articles The PTEN inhibitor bisperoxovanadium enhances myelination by amplifying IGF-1 signaling in rat and human oligodendrocyte progenitors. Glia. 2014 Jan;62(1):64-77 Authors: De Paula ML, Cui QL, Hossain S, Antel J, Almazan G Abstract Oligodendrocytes (OLGs) produce and maintain myelin in the central nervous system (CNS). In the demyelinating autoimmune disease multiple sclerosis, OLGs are damaged and those remaining fail to fully remyelinate CNS lesions. Therefore, current therapies directed to restrain the inflammation process with approaches that protect and reconstitute oligodendrocyte density would be essential to pave the way of myelin repair. A critical signal for oligodendrocytes is insulin-like growth factor-1 (IGF-1), which promotes their development and ultimately myelin formation. PTEN inhibits the phosphoinositide 3-kinase (PI3K)/Akt signaling, a convergence downstream pathway for growth factors such as IGF-1. In this report, we temporarily inhibited PTEN activity by treating rat and human oligodendrocyte progenitors (OLPs) cultured alone or with dorsal root ganglion neurons (DRGNs) with bisperoxovanadium (phen). Our findings show that phen potentiates IGF-1 actions by increasing proliferation of OLPs in a concentration-dependent manner, and caused a sustained and time-dependent activation of the main pathways: PI3K/Akt/mammalian target of rapamycin (mTOR) and MEK/ERK. At low concentrations, IGF-1 and phen stimulated the differentiation of rat and human OLPs. Concordantly, the PTEN inhibitor together with IGF-1 robustly augmented myelin basic protein accumulation in rat newborn and human fetal OLGs co-cultured with DRGNs in a longer timeframe by promoting the elaboration of organized myelinated fibers as evidenced by confocal microscopy. Thus, our results suggest that a transient suppression of a potential barrier for myelination in combination with other therapeutic approaches including growth factors may be promising to improve the functional recovery of CNS injuries. PMID: 24166839 [PubMed - indexed for MEDLINE]
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Related Articles Activation of NOD2/RIPK2 pathway induces mitochondrial injury to oligodendrocyte precursor cells in vitro and CNS demyelination in vivo. J Neuroimmunol. 2013 Dec 15;265(1-2):51-60 Authors: Natarajan C, Yao SY, Zhang F, Sriram S Abstract We examined the activation of innate immune pathway mediated by nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in oligodendrocyte precursor cells (OPCs). We show that activation of NOD2 by ligand peptidoglycan (PGN) leads to the recruitment and phosphorylation of receptor-interacting serine/threonine kinase 2 (RIPK2). Phosphorylation of RIPK2 is followed by phosphorylation of neuronal nitric oxide synthase (nNOS), increase in NOS activity and subsequent accumulation of nitric oxide (NO) mediated N-tyrosinylated compounds in OPCs. The reversal of NOS activity by the nNOS inhibitor 7-nitroindazole (7-NI), but not by the iNOS inhibitor L-canavanine, supported the conclusion that the increased NOS activity was due to the selective activation of nNOS in OPCs. In addition, NO mediated injury to OPC was reflected in reduction in activity of respiratory enzymes such as complex I and IV, decrease in mitochondrial membrane potential and release of cytochrome-C from mitochondria. Furthermore, intracerebral injection of PGN into corpus callosum (CC) of rats led to the development of demyelination, which appeared as early as by day 3 post-injection, and involved the trunk of the CC by day 14. Accumulation of N-tyrosinylated proteins was seen in oligodendrocytes in regions of the CC which were in close proximity to the injection site. Taken together, these results suggest that PGN induced formation of NO, mitochondrial dysfunction and accumulation of N-tyrosinylated proteins in oligodendrocytes are likely mediators of central nervous system demyelination. PMID: 24169446 [PubMed - indexed for MEDLINE]
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Related Articles iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF. Nat Commun. 2013;4:2597 Authors: Laterza C, Merlini A, De Feo D, Ruffini F, Menon R, Onorati M, Fredrickx E, Muzio L, Lombardo A, Comi G, Quattrini A, Taveggia C, Farina C, Cattaneo E, Martino G Abstract The possibility of generating neural stem/precursor cells (NPCs) from induced pluripotent stem cells (iPSCs) has opened a new avenue of research that might nurture bench-to-bedside translation of cell transplantation protocols in central nervous system myelin disorders. Here we show that mouse iPSC-derived NPCs (miPSC-NPCs)-when intrathecally transplanted after disease onset-ameliorate clinical and pathological features of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Transplanted miPSC-NPCs exert the neuroprotective effect not through cell replacement, but through the secretion of leukaemia inhibitory factor that promotes survival, differentiation and the remyelination capacity of both endogenous oligodendrocyte precursors and mature oligodendrocytes. The early preservation of tissue integrity limits blood-brain barrier damage and central nervous system infiltration of blood-borne encephalitogenic leukocytes, ultimately responsible for demyelination and axonal damage. While proposing a novel mechanism of action, our results further expand the therapeutic potential of NPCs derived from iPSCs in myelin disorders. PMID: 24169527 [PubMed - indexed for MEDLINE]
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Related Articles Cognitive fatigue in individuals with multiple sclerosis undergoing immunoablative therapy and hematopoietic stem cell transplantation. J Neurol Sci. 2014 Jan 15;336(1-2):132-7 Authors: Berard JA, Bowman M, Atkins HL, Freedman MS, Walker LA Abstract BACKGROUND: Fatigue presents as a significant problem in multiple sclerosis (MS). Cognitive fatigue (CF) can be defined as a decrease in, or inability to maintain task performance throughout the duration of a continuous cognitive task. CF was evaluated using the Paced Auditory Serial Addition Test (PASAT) both pre- and post-immunoablation and hematopoietic stem cell transplantation (IA-HSCT) over a 3-year follow-up period. The magnitude of CF was examined and the impact of scoring methodology was evaluated. METHODS: Twenty-three individuals with rapidly progressive MS and poor prognosis underwent high dose immunosuppression and subsequent HSCT. Individuals completed the 3″ and 2″ PASAT at baseline and every 6 months thereafter over a period of 36 months. As scoring methodology can impact its sensitivity to CF, the PASAT was scored according to three scoring methods. RESULTS: CF was noted across all three scoring methods at baseline and at the majority of time points post-IA-HSCT on both the 3″ and 2″ PASAT. The magnitude of CF remained consistent both pre-and post-IA-HSCT. CONCLUSIONS: While results suggest that the procedure itself does not ameliorate an individual's susceptibility to CF; neither does it seem to negatively impact levels of CF. As such, results support the notion that the IA-HSCT procedure, despite its aggressive nature, does not exacerbate CF in this particular sample. PMID: 24189209 [PubMed - indexed for MEDLINE]
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Related Articles Hepatocyte growth factor regulates immune reactions caused by transplantation and autoimmune diseases. Yakugaku Zasshi. 2013;133(11):1159-67 Authors: Iwasaki T, Shibasaki S Abstract Hepatocyte growth factor (HGF) was first identified and cloned as a mitogenic protein for hepatocytes, and subsequent studies revealed that HGF has multiple biological effects on a wide variety of cells, including mitogenic, motogenic, morphogenic, anti-apoptotic, and angiogenic activities. It plays roles in organizing tissues during development and regeneration. HGF may be applied for the treatment of acute onset diseases such as fulminant hepatitis, myocardial infarction, acute renal failure, cerebral infarction, and chronic diseases like liver cirrhosis, chronic renal failure, pulmonary fibrosis, cardiomyopathy, and arteriosclerosis obliterans. HGF also has immunomodulatory activities and we previously demonstrated that its administration inhibited acute graft-versus-host disease (GVHD) after treatment with hematopoietic stem cell transplantation. We also demonstrated that HGF inhibited lupus nephritis induced by chronic GVHD and dermal sclerosis in systemic sclerosis using model mice. More than 7 hundred thousand patients suffer from rheumatoid arthritis (RA) in Japan. Although the prognosis of these patients has improved by the treatment of biological agents such as TNF-α and IL-6 blockers, there remain many for whom these agents have not proved beneficial. Recently, using RA model mice, we demonstrated that the HGF antagonist, NK4, can block disease progression of RA through its anti-angiogenic and immunomodulatory actions. In this review article, we discuss the possible roles of HGF signaling for the treatment of immunological reactions in transplantation and autoimmune diseases. PMID: 24189557 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of umbilical cord and bone marrow-derived mesenchymal stem cells in a patient with relapsing-remitting multiple sclerosis. Cell Adh Migr. 2013 Sep-Oct;7(5):404-7 Authors: Hou ZL, Liu Y, Mao XH, Wei CY, Meng MY, Liu YH, Zhuyun Yang Z, Zhu H, Short M, Bernard C, Xiao ZC Abstract There is currently great interest in the use of mesenchymal stem cells as a therapy for multiple sclerosis with potential to both ameliorate inflammatory processes as well as improve regeneration and repair. Although most clinical studies have used autologous bone marrow-derived mesenchymal stem cells, other sources such as allogeneic umbilical cord-derived cells may provide a more accessible and practical supply of cells for transplantation. In this case report we present the treatment of aggressive multiple sclerosis with multiple allogenic human umbilical cord-derived mesenchymal stem cell and autologous bone marrow-derived mesenchymal stem cells over a 4 y period. The treatments were tolerated well with no significant adverse events. Clinical and radiological disease appeared to be suppressed following the treatments and support the expansion of mesenchymal stem cell transplantation into clinical trials as a potential novel therapy for patients with aggressive multiple sclerosis. PMID: 24192520 [PubMed - indexed for MEDLINE]
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Related Articles Neurotrophin 3 transduction augments remyelinating and immunomodulatory capacity of neural stem cells. Mol Ther. 2014 Feb;22(2):440-50 Authors: Yang J, Yan Y, Xia Y, Kang T, Li X, Ciric B, Xu H, Rostami A, Zhang GX Abstract Neural stem cells (NSCs) have therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS); however, to date, their use has resulted in only limited clinical and pathological improvement. To enhance their therapeutic capacity, in the present study, we transduced bone marrow-derived NSCs (BM-NSCs) with neurotrophin 3 (NT-3), a potent neurotrophic factor that is both neuroprotective and immunomodulatory. We found that BM-NSCs transduced with NT-3 reduced central nervous system (CNS) inflammation and neurological deficits in ongoing EAE significantly more than conventional NSC therapy, and, in addition, had the following advantages: (i) enhanced BM-NSC proliferation and differentiation into oligodendrocytes and neurons, as well as inhibited differentiation into astrocytes, thus promoting remyelination and neuronal repopulation, and reducing astrogliosis; (ii) enhanced anti-inflammatory capacity of BM-NSCs, thus more effectively suppressing CNS inflammation and accelerating remyelination; (iii) the easy accessibility of BM-NSCs provides another advantage over brain-derived NSCs for MS therapy; and (iv) a novel Tet-on system we used enables efficient control of NT-3 expression. Thus, our study provides a novel approach to break the vicious inflammation-demyelination cycle, and could pave the way to an easily accessible and highly effective therapy for CNS inflammatory demyelination. PMID: 24247929 [PubMed - indexed for MEDLINE]
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Related Articles The molecular study of IFNβ pleiotropic roles in MS treatment. Iran J Neurol. 2013;12(4):149-56 Authors: Kay M, Hojati Z, Dehghanian F Abstract Multiple sclerosis (MS) is one of the most important autoimmune diseases recognized by demyelination and axonal lesion. It is the most common cause of disability in the young population. Various immunomodulatory and immunosuppressive therapies, including different formulations of interferon beta (IFNβ), glatiramer acetate (GA), mitoxantrone, and natalizumab are available for this disease. However, interferon has been the best prescribed. Although the precise mechanism of IFNβ is unclear, many studies indicate some potential mechanism including blocking T cells activation, controlling pro- and anti-inflammatory cytokine secretion, preventing activated immune cell migration through BBB, and inducing repair activity of damaged nerve cells by differentiating neural stem cells into oligodendrocytes. These molecular mechanisms have significant roles in IFNβ therapy. More researches are required in order for us to comprehend the mechanism of action of IFNβ, and improve and develop drugs for more efficient MS treatment. PMID: 24250925 [PubMed]
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Related Articles Immunoablation of cells expressing the NG2 chondroitin sulphate proteoglycan. J Anat. 2014 Feb;224(2):216-27 Authors: Leoni G, Rattray M, Fulton D, Rivera A, Butt AM Abstract Expression of the transmembrane NG2 chondroitin sulphate proteoglycan (CSPG) defines a distinct population of NG2-glia. NG2-glia serve as a regenerative pool of oligodendrocyte progenitor cells in the adult central nervous system (CNS), which is important for demyelinating diseases such as multiple sclerosis, and are a major component of the glial scar that inhibits axon regeneration after CNS injury. In addition, NG2-glia form unique neuron-glial synapses with unresolved functions. However, to date it has proven difficult to study the importance of NG2-glia in any of these functions using conventional transgenic NG2 'knockout' mice. To overcome this, we aimed to determine whether NG2-glia can be targeted using an immunotoxin approach. We demonstrate that incubation in primary anti-NG2 antibody in combination with secondary saporin-conjugated antibody selectively kills NG2-expressing cells in vitro. In addition, we provide evidence that the same protocol induces the loss of NG2-glia without affecting astrocyte or neuronal numbers in cerebellar brain slices from postnatal mice. This study shows that targeting the NG2 CSPG with immunotoxins is an effective and selective means for killing NG2-glia, which has important implications for studying the functions of these enigmatic cells both in the normal CNS, and in demyelination and degeneration. PMID: 24252088 [PubMed - indexed for MEDLINE]
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Related Articles Bone marrow mesenchymal stromal cells isolated from multiple sclerosis patients have distinct gene expression profile and decreased suppressive function compared with healthy counterparts. Cell Transplant. 2013 Nov 20; Authors: de Oliveira GL, de Lima KW, Colombini AM, Pinheiro DG, Panepucci RA, Palma PV, Brum DG, Covas DT, Simões BP, de Oliveira MC, Donadi EA, Malmegrim KC Abstract Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system, due to immune reaction against myelin proteins. Multipotent mesenchymal stromal cells (MSCs) present immunosuppressive effects and have been used for the treatment of autoimmune diseases. In our study, gene expression profile and in vitro immunomodulatory function tests were used to compare bone marrow?derived MSCs obtained from MS patients, at pre? and post?autologous hematopoietic stem cell transplantation (AHSCT), with those from healthy donors. Patient MSCs comparatively exhibited: i) senescence in culture, ii) similar osteogenic and adipogenic differentiation potential, iii) decreased expression of CD105, CD73, CD44 and HLA?A/B/C molecules, iv) distinct transcription profile at pre?AHSCT compared with control MSCs, yielding 618 differentially expressed genes, including the downregulation of TGFB1 and HGF genes and modulation of the FGF and HGF signaling pathways, v) reduced antiproliferative effect when pre?AHSCT MSCs were cocultured with allogeneic T?lymphocytes, vi) decreased secretion of IL?10 and TGF?β in supernatants of both cocultures (pre? and post?AHSCT MSCs), vii) similar percentages of regulatory cells recovered after MSC cocultures. The transcriptional profile of patient MSCs isolated six months post?transplantation was closer to pre?AHSCT samples than from healthy MSCs. Considering that patient MSCs exhibited phenotypic changes, distinct transcriptional profile and functional defects implicated in MSC immunomodulatory and immunosuppressive activity, we suggest that further MS clinical studies should be conducted using allogeneic bone marrow MSCs derived from healthy donors. We also demonstrated that treatment of MS patients with AHSCT does not reverse the transcriptional and functional alterations observed in patient MSCs. PMID: 24256874 [PubMed - as supplied by publisher]
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Related Articles RECENT ADVANCES IN MESENCHYMAL STEM CELL IMMUNOMODULATION. THE ROLE OF MICROVESICLES. Cell Transplant. 2013 Nov 21; Authors: Fierabracci A, Del Fattore A, Luciano R, Muraca M, Teti A, Muraca M Abstract Mesenchymal stem cells are the most widely used cell phenotype for therapeutic applications, the main reasons being their well-established abilities to promote regeneration of injured tissues and to modulate immune responses. Efficacy was reported in the treatment of several animal models of inflammatory and autoimmune diseases and, in clinical settings, for the management of disorders such as GVHD, Systemic Lupus Erythematosus, multiple sclerosis and inflammatory bowel disease. The effects of mesenchymal stem cells are believed to be largely mediated by paracrine signals, and several secreted molecules have been identified as contributors to the net biological effect. Recently, it has been recognized that bioactive molecules can be shuttled from cell to cell packed in microvesicles, tiny portions of cytoplasm surrounded by a membrane. Coding and non-coding RNAs are also carried in such microvesicles, transferring relevant biological activity to target cells. Several reports indicate that the regenerative effect of mesenchymal stem cells can be reproduced by microvesicles isolated from their culture medium. More recent evidence suggests that the immunomodulatory effects of mesenchymal stem cells are also at least partially mediated by secreted microvesicles. These findings allow better understanding of the mechanisms involved in cell-to-cell interaction and may have interesting implications for the development of novel therapeutic tools in place of the parent cells. PMID: 24268069 [PubMed - as supplied by publisher]
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Related Articles IFNγ-stimulated dendritic cell exosomes as a potential therapeutic for remyelination. J Neuroimmunol. 2014 Jan 15;266(1-2):12-23 Authors: Pusic AD, Pusic KM, Clayton BL, Kraig RP Abstract Dendritic cells (DCs) release exosomes with different characteristics based on stimulus. Here, we showed that DC cultures stimulated with low-level IFNγ released exosomes (IFNγ-DC-Exos) that contained microRNA species that can increase baseline myelination, reduce oxidative stress, and improve remyelination following acute lysolecithin-induced demyelination. Furthermore, nasally administered IFNγ-DC-Exos increased CNS myelination in vivo. IFNγ-DC-Exos were preferentially taken up by oligodendrocytes, suggesting that they directly impact oligodendrocytes to increase myelination. Thus, our results show great potential for use of these IFNγ-DC-Exos as a therapeutic to promote remyelination in multiple sclerosis and dysmyelinating syndromes. PMID: 24275061 [PubMed - indexed for MEDLINE]
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Related Articles Protocol to isolate a large amount of functional oligodendrocyte precursor cells from the cerebral cortex of adult mice and humans. PLoS One. 2013;8(11):e81620 Authors: Medina-Rodríguez EM, Arenzana FJ, Bribián A, de Castro F Abstract During development, oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), a cell type that is a significant proportion of the total cells (3-8%) in the adult central nervous system (CNS) of both rodents and humans. Adult OPCs are responsible for the spontaneous remyelination that occurs in demyelinating diseases like Multiple Sclerosis (MS) and they constitute an interesting source of cells for regenerative therapy in such conditions. However, there is little data regarding the neurobiology of adult OPCs isolated from mice since an efficient method to isolate them has yet to be established. We have designed a protocol to obtain viable adult OPCs from the cerebral cortex of different mouse strains and we have compared its efficiency with other well-known methods. In addition, we show that this protocol is also useful to isolate functional OPCs from human brain biopsies. Using this method we can isolate primary cortical OPCs in sufficient quantities so as to be able to study their survival, maturation and function, and to facilitate an evaluation of their utility in myelin repair. PMID: 24303061 [PubMed - indexed for MEDLINE]
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Related Articles Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica. Ann Neurol. 2014 Mar;75(3):447-53 Authors: Greco R, Bondanza A, Vago L, Moiola L, Rossi P, Furlan R, Martino G, Radaelli M, Martinelli V, Carbone MR, Lupo Stanghellini MT, Assanelli A, Bernardi M, Corti C, Peccatori J, Bonini C, Vezzulli P, Falini A, Ciceri F, Comi G Abstract Neuromyelitis optica is a rare neurological autoimmune disorder characterized by a poor prognosis. Immunosuppression can halt disease progression, but some patients are refractory to multiple treatments, experiencing frequent relapses with accumulating disability. Here we report on durable clinical remissions after allogeneic hematopoietic stem cell transplantation in 2 patients suffering from severe forms of the disease. Immunological data evidenced disappearance of the pathogenic antibodies and regeneration of a naive immune system of donor origin. These findings correlated with evident clinical and radiological improvement in both patients, warranting extended clinical trials to investigate this promising therapeutic option. PMID: 24318127 [PubMed - indexed for MEDLINE]
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Related Articles Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia. 2014 Feb;62(2):284-99 Authors: Pusic AD, Kraig RP Abstract Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression. However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cells-both under control conditions and after acute demyelination. Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination. PMID: 24339157 [PubMed - indexed for MEDLINE]
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Related Articles Evaluation of lovastatin effects on expression of anti-apoptotic Nrf2 and PGC-1α genes in neural stem cells treated with hydrogen peroxide. Mol Neurobiol. 2014 Jun;49(3):1364-72 Authors: Abdanipour A, Tiraihi T, Noori-Zadeh A, Majdi A, Gosaili R Abstract Reactive oxygen species and oxidative stress are associated with various cell processes, including cell survival and apoptosis. Oxidative stress has been implicated in the pathogenesis of several neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). In the present study, we evaluated the effects of lovastatin chemoprotection against hydrogen peroxide-induced oxidative stress in bone marrow stromal cell-derived neural stem cells (BMSC-derived NSCs) and whether it has protective effects. BMSC-derived NSCs were pretreated with different doses of lovastatin for 48 h and then exposed to 125 μM H2O2 for 30 min. Using MTT, TUNEL assay, and real-time RT-PCR, we evaluated the effects of lovastatin on cell survival, apoptosis, and PGC-1α and Nrf2 expression rates in pretreated BMSC-derived NSCs compared to control groups. Results showed that apoptosis rate in the lovastatin-pretreated BMSC-derived NSCs was significantly decreased compared to the control group. Our findings suggest that lovastatin protects NSCs against oxidative stress-induced cell death, and therefore, it may be used to promote the survival rate of NSCs and can be a candidate for treatment of oxidative stress-mediated neurological diseases. PMID: 24390568 [PubMed - in process]
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Related Articles Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression. EMBO Mol Med. 2014 Mar;6(3):322-34 Authors: Chen C, Akiyama K, Yamaza T, You YO, Xu X, Li B, Zhao Y, Shi S Abstract Bone marrow mesenchymal stem cells (BMMSCs) are capable of differentiating into multiple cell types and regulating immune cell response. However, the mechanisms that govern the immunomodulatory properties of BMMSCs are still not fully elucidated. Here we show that telomerase-deficient BMMSCs lose their capacity to inhibit T cells and ameliorate the disease phenotype in systemic sclerosis mice. Restoration of telomerase activity by telomerase reverse transcriptase (TERT) transfection in TERT(-/-) BMMSCs rescues their immunomodulatory functions. Mechanistically, we reveal that TERT, combined with β-catenin and BRG1, serves as a transcriptional complex, which binds the FAS ligand (FASL) promoter to upregulate FASL expression, leading to an elevated immunomodulatory function. To test the translational value of these findings in the context of potential clinical therapy, we used aspirin treatment to upregulate telomerase activity in BMMSCs, and found a significant improvement in the immunomodulatory capacity of BMMSCs. Taken together, these findings identify a previously unrecognized role of TERT in improving the immunomodulatory capacity of BMMSCs, suggesting that aspirin treatment is a practical approach to significantly reduce cell dosage in BMMSC-based immunotherapies. PMID: 24401839 [PubMed - indexed for MEDLINE]
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Related Articles Beneficial actions of the anti-inflammatory dimethyl fumarate in glioblastomas. Surg Neurol Int. 2013;4:160 Authors: Ghods AJ, Glick R, Braun D, Feinstein D Abstract BACKGROUND: Dimethylfumarate (DMF), a drug used in the treatment of psoriasis and multiple sclerosis, has been shown to limit the growth of melanoma cells. The ability of DMF to inhibit the Rel protein has been used to explain the antioncogenic properties of this drug. Studies analyzing the effect of DMF in gliomas are limited. Therefore, we investigated the potential antitumor effects of DMF by assessing its effects on proliferation, cell death, and differentiation in gliomas in several glioma models. METHODS: Mouse glioma Gl261, human glioblastoma A172 and human glioblastoma cells from patients were exposed to DMF at therapeutic concentrations (100 μM) and supratherapeutic concentrations (300 μM) and studies to assess proliferation, cellular lysis, and differentiation undertaken. The 5-bromo-2'-deoxyuridine (BRDU) proliferation assay and lactate dehydrogenase LDH cell lysis assay were used. Immunocytochemistry was used to assess differentiation: CD133 (stem cell marker), Nestin (progenitor marker), Sox2 (progenitor marker), β-tubulin III (neuronal marker), glial fibrillary acidic protein (astrocytic marker), and myelin basic protein (oligodendrocytic marker). We also assessed cellular expression of nuclear factor kappa B (NF-κB) via immunocytochemistry. RESULTS: Proliferation significantly decreased and tumor cell lysis significantly increased in all tumor cell lines after exposure to DMF. The human glioblastoma cells expressed the Neuronal Stem Cell marker CD133, Progenitor Cell markers, Neuronal and Astrocytic Cell Markers in vitro. When exposed to DMF, a drastic decline in CD133 expression was observed in addition to a decrease in the expression of NF-κB. CONCLUSION: DMF appears to have a promising role in the treatment of malignant brain neoplasms. DMF reduced proliferation rate, generated cell lysis, decreased the expression of NF-κB, and restricted the growth of CD133 cells in gliomas. This suggests that DMF may be considered for further antitumor studies, and provide a new treatment modality for brain tumors. PMID: 24404403 [PubMed]
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Related Articles Comparison of human adult stem cells from adipose tissue and bone marrow in the treatment of experimental autoimmune encephalomyelitis. Stem Cell Res Ther. 2014;5(1):2 Authors: Semon JA, Maness C, Zhang X, Sharkey SA, Beuttler MM, Shah FS, Pandey AC, Gimble JM, Zhang S, Scruggs BA, Strong AL, Strong TA, Bunnell BA Abstract INTRODUCTION: While administration of ex vivo culture-expanded stem cells has been used to study immunosuppressive mechanisms in multiple models of autoimmune diseases, less is known about the uncultured, nonexpanded stromal vascular fraction (SVF)-based therapy. The SVF is composed of a heterogeneous population of cells and has been used clinically to treat acute and chronic diseases, alleviating symptoms in a range of tissues and organs. METHODS: In this study, the ability of human SVF cells was compared with culture-expanded adipose stem cells (ASCs) and bone-derived marrow stromal cells (BMSCs) as a treatment of myelin oligodendrocyte glycoprotein (35-55)-induced experimental autoimmune encephalitis in C57Bl/6J mice, a well-studied multiple sclerosis model (MS). A total of 1×10⁶ BMSCs, ASCs, or SVF cells were administered intraperitoneally concomitantly with the induction of disease. Mice were monitored daily for clinical signs of disease by three independent, blinded investigators and rated on a scale of 0 to 5. Spinal cords were obtained after euthanasia at day 30 and processed for histological staining using luxol fast blue, toluidine blue, and hematoxylin and eosin to measure myelin and infiltrating immune cells. Blood was collected from mice at day 30 and analyzed by enzyme-linked immunosorbent assay to measure serum levels of inflammatory cytokines. RESULTS: The data indicate that intraperitoneal administration of all cell types significantly ameliorates the severity of disease. Furthermore, the data also demonstrate, for the first time, that the SVF was as effective as the more commonly cultured BMSCs and ASCs in an MS model. All cell therapies also demonstrated a similar reduction in tissue damage, inflammatory infiltrates, and sera levels of IFNγ and IL-12. While IFNγ levels were reduced to comparable levels between treatment groups, levels of IL-12 were significantly lower in SVF-treated than BMSC-treated or ASC-treated mice. CONCLUSIONS: Based on these data, it is evident that SVF cells have relevant therapeutic potential in an animal model of chronic MS and might represent a valuable tool for stem cell-based therapy in chronic inflammatory disease of the central nervous system. SVF offers advantages of direct and rapid isolation procedure in a xenobiotic-free environment. PMID: 24405805 [PubMed - in process]
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Related Articles T cell mediated suppression of neurotropic coronavirus replication in neural precursor cells. Virology. 2014 Jan 20;449:235-43 Authors: Plaisted WC, Weinger JG, Walsh CM, Lane TE Abstract Neural precursor cells (NPCs) are the subject of intense investigation for their potential to treat neurodegenerative disorders, yet the consequences of neuroinvasive virus infection of NPCs remain unclear. This study demonstrates that NPCs support replication following infection by the neurotropic JHM strain of mouse hepatitis virus (JHMV). JHMV infection leads to increased cell death and dampens IFN-γ-induced MHC class II expression. Importantly, cytokines secreted by CD4+ T cells inhibit JHMV replication in NPCs, and CD8+ T cells specifically target viral peptide-pulsed NPCs for lysis. Furthermore, treatment with IFN-γ inhibits JHMV replication in a dose-dependent manner. Together, these findings suggest that T cells play a critical role in controlling replication of a neurotropic virus in NPCs, a finding which has important implications when considering immune modulation for NPC-based therapies for treatment of human neurologic diseases. PMID: 24418558 [PubMed - indexed for MEDLINE]
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Related Articles Osthole augments therapeutic efficiency of neural stem cells-based therapy in experimental autoimmune encephalomyelitis. J Pharmacol Sci. 2014;124(1):54-65 Authors: Gao Z, Wen Q, Xia Y, Yang J, Gao P, Zhang N, Li H, Zou S Abstract The therapeutic potential of adult neural stem cells (NSCs)-derived from bone marrow (BM) has been recently described in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis; however, the beneficial effects are modest due to their marginal anti-inflammatory capacity. To overcome this weakness and endow BM-NSC therapy with profound anti-inflammatory capacity, in this study we pretreated EAE mice with osthole, a natural coumarin with a broad spectrum of pharmacological activities, including anti-inflammation, immunomodulation, and neuroprotection, before NSC-application and continued throughout the study. We found that osthole conferred a potent anti-inflammatory capacity to this BM-NSC therapy, thus more profoundly suppressing ongoing EA and exhibiting significant advantages over conventional NSC-therapy as follows: 1) Enhanced anti-inflammatory effect, thus improving survival environment for engrafted BM-NSCs and protecting myelin sheaths from further demyelination; 2)Drove transplanted (exogenous) BM-NSCs to differentiate into more oligodendrocytes and neurons but inhibited differentiation into astrocytes, thus promoting remyelination and axonal growth, and reducing astrogliosis; and 3) augmented CNS neurotrophic support thus promoted resident (endogenous) repair of myelin/axonal damage. These effects make the BM-NSCs-based therapy a more promising approach to enhance remyelination and neuronal repopulation, thus more effectively promoting anatomic and functional recovery from neurological deficits. PMID: 24441773 [PubMed - indexed for MEDLINE]
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Related Articles Established and novel disease-modifying treatments in multiple sclerosis. J Intern Med. 2014 Apr;275(4):350-63 Authors: Cross AH, Naismith RT Abstract Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease-modifying therapies introduced in the 1990s, the beta-interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha-4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long-term postmarketing efficacy and safety data in a general MS population. Because of this lack of long-term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit-to-risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e.g. fingolimod or natalizumab if JC virus antibody-negative). The aim of this review is to discuss the clinical benefits, mechanisms of action, safety profiles and monitoring strategies of current MS disease-modifying therapies in clinical practice and of those expected to enter the market in the near future. PMID: 24444048 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model. PLoS One. 2014;9(1):e85007 Authors: Zhang X, Bowles AC, Semon JA, Scruggs BA, Zhang S, Strong AL, Gimble JM, Bunnell BA Abstract Multiple sclerosis (MS), characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs) for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE), a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression. PMID: 24465465 [PubMed - indexed for MEDLINE]
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Related Articles Integrin/Chemokine receptor interactions in the pathogenesis of experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol. 2014 Jun;9(3):438-45 Authors: Banisadr G, Schwartz SR, Podojil JR, Piccinini LA, Lanker S, Miller SD, Miller RJ Abstract Excessive infiltration of leukocytes and the elaboration of inflammatory cytokines are believed to be responsible for the observed damage to neurons and oligodendrocytes during multiple sclerosis (MS). Blocking adhesion molecules or preventing the effects of chemotactic mediators such as chemokines can be exploited to prevent immune cell recruitment to inflamed tissues. An anti-α4 integrin antibody (anti-VLA-4mAb/natalizumab (Tysabri®)) has been used as a treatment for MS and reduces leukocyte influx into the brain. In patients, anti-VLA-4 reduces relapses and disability progression. However, its mechanism of action in the brain is not completely understood. The anti-VLA-4mAb was demonstrated to mobilize hematopoietic progenitor cells. Interestingly, the chemokine SDF-1/CXCL12 and its receptor CXCR4 are also key factors regulating the migration of hematopoietic stem cells. Moreover, studies have revealed a crosstalk between SDF-1/CXCR4 and VLA-4 signaling in regulating cell migration. In this study, we address the effects of anti-VLA-4 on chemokine signaling in the brain during MS. We assessed the ability of anti-VLA-4 to regulate Experimental Autoimmune Encephalomyelitis (EAE) and chemokine/receptor signaling. Preclinical administration of anti-VLA-4 delayed clinical signs of EAE. We found that anti-VLA-4 treatment reduced chemokine expression. In order to further explore the interaction of anti-VLA-4 with chemokine/receptor signaling we used dual color transgenic mice. After EAE induction, the expression of both SDF-1/CXCL12 and CXCR4 receptor was upregulated, treatment with anti-VLA-4 inhibited this effect. The effects of anti-VLA-4 on chemokine signaling in the CNS may be of importance when considering its mechanism of action and understanding the pathogenesis of EAE. PMID: 24477403 [PubMed - in process]
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Related Articles Transplantation of Fas-deficient or wild-type neural stem/progenitor cells (NPCs) is equally efficient in treating experimental autoimmune encephalomyelitis (EAE). Am J Transl Res. 2014;6(2):119-28 Authors: Hackett C, Knight J, Mao-Draayer Y Abstract Studies have shown that neural stem/progenitor cell (NPC) transplantation is beneficial in experimental autoimmune encephalomyelitis (EAE), an established animal model of multiple sclerosis (MS). It is unclear whether NPCs have the ability to integrate into the host CNS to replace lost cells or if their main mechanism of action is via bystander immunomodulation. Understanding the mechanisms by which NPCs exert their beneficial effects as well as exploring methods to increase post-transplantation survival and differentiation is critical to advancing this treatment strategy. Using the EAE model and Fas-deficient (lpr) NPCs, we investigated the effects of altering the Fas system in NPC transplantation therapy. We show that transplantation of NPCs into EAE mice ameliorates clinical symptoms with greater efficacy than sham treatments regardless of cell type (wt or lpr). NPC transplantation via retro-orbital injections significantly decreased inflammatory infiltrates at the acute time point, with a similar trend at the chronic time point. Both wt and lpr NPCs injected into mice with EAE were able to home to sites of CNS inflammation in the periventricular brain and lumbar spinal cord. Both wt and lpr NPCs have the same capacity for inducing apoptosis of Th1 and Th17 cells, and minimal numbers of NPCs entered the CNS. These cells did not express terminal differentiation markers, suggesting that NPCs exert their effects mainly via bystander peripheral immunomodulation. PMID: 24489991 [PubMed]
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Related Articles The anti-VLA-4 antibody natalizumab induces erythroblastaemia in the majority of the treated patients with multiple sclerosis. Mult Scler. 2014 Feb 3;20(9):1269-1272 Authors: Robier C, Amouzadeh-Ghadikolai O, Bregant C, Diez J, Melinz K, Neubauer M, Quasthoff S Abstract The presence of erythroblasts in the peripheral blood is generally associated with severe underlying disorders. The anti-very late antigen-4 (anti-VLA-4) antibody natalizumab, which is approved for treatment of multiple sclerosis, mediates an increase in circulating haematopoietic stem cells and may also trigger erythroblastaemia. We investigated the prevalence of erythroblastaemia in sequential blood smears of 14 natalizumab-treated and 14 interferon-treated patients with multiple sclerosis. Erythroblastaemia was found in 13 natalizumab-treated subjects (93%), whereas all controls were negative (p<0.0001). Knowledge of this frequent side effect is crucial for the correct interpretation of blood smears in natalizumab-treated patients and to avoid unnecessary diagnostic procedures. PMID: 24493472 [PubMed - as supplied by publisher]
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Related Articles Feasibility of cell therapy in multiple sclerosis: a systematic review of 83 studies. Int J Hematol Oncol Stem Cell Res. 2013;7(1):15-33 Authors: Ardeshiry Lajimi A, Hagh MF, Saki N, Mortaz E, Soleimani M, Rahim F Abstract Multiple Sclerosis is an inflammatory disease of the central nervous system in which T cells experience a second phase of activation, which ultimately leads to axonal demyelination and neurological disability. The recent advances in stem cell therapies may serve as potential treatments for neurological disorders. There are broad types of stem cells such as neural, embryonic, mesenchymal and hematopoietic stem cells with unprecedented hope in treating many debilitating diseases. In this paper we will review the substantial literature regarding experimental and clinical use of these stem cells and possible mechanisms in the treatment of MS. These results may pave the road for the utilization of stem cells for the treatment of MS. PMID: 24505515 [PubMed]
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Related Articles Future treatment approaches to multiple sclerosis. Handb Clin Neurol. 2014;122:563-77 Authors: Derwenskus J, Lublin FD Abstract The modern treatment era for multiple sclerosis (MS) began in 1993 with the approval of the first disease-modifying agent. Since then the field has greatly expanded, with 10 therapies currently approved to treat MS. These treatments are effective to reduce relapses and changes on MRI, and slow disability. However, despite these medications some patients continue to have exacerbations, accumulate disability, and develop progressive disease due to partial effectiveness. New molecules with novel mechanisms of action and targets are being explored. Hopefully these agents will yield even greater efficacy without significant safety concerns. As more aggressive therapies are available to treat MS, the goals and expectations of treatment are also likely to change. Some of the emerging therapies, including alemtuzumab, daclizumab, rituximab, ocrelizumab, laquinimod, estriol, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), vitamin D, and stem cell transplantation, will be discussed in this chapter. In the future, therapies with different mechanisms may be combined, but this will need to be evaluated in clinical trials. Neuroprotection and repair definitely warrant further study. The future of MS treatment is very exciting, especially as our armamentarium expands. PMID: 24507535 [PubMed - indexed for MEDLINE]
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Related Articles Recent advances in stem cells and regenerative medicine. QJM. 2014 Apr;107(4):251-2 Authors: Forbes SJ PMID: 24509234 [PubMed - indexed for MEDLINE]
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Related Articles Intraspinal transplantation of mouse and human neural precursor cells. Curr Protoc Stem Cell Biol. 2013;26:Unit 2D.16. Authors: Weinger JG, Chen L, Coleman R, Leang R, Plaisted WC, Loring JF, Lane TE Abstract This unit describes the preparation and transplantation of human neural precursor cells (hNPCs) and mouse neural precursor cells (mNPCs) into the thoracic region of the mouse spinal cord. The techniques in this unit also describe how to prepare the mouse for surgery by performing a laminectomy to expose the spinal cord for transplantation. NPCs genetically labeled with eGFP transplanted into the spinal cord of a mouse following viral-mediated demyelination can efficiently be detected via eGFP expression. Transplantation of these cells into the spinal cord is an efficacious way to determine their effects in neurological disorders such as multiple sclerosis, Alzheimer's disease, and spinal cord injury. PMID: 24510791 [PubMed - indexed for MEDLINE]
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Related Articles T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014 Mar 3;124(3):1168-72 Authors: Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, de Paula Alves Sousa A, Griffith LM, Lim N, Nash RA, Turka LA Abstract Autologous hematopoietic stem cell transplantation (HSCT) is commonly employed for hematologic and non-hematologic malignancies. In clinical trials, HSCT has been evaluated for severe autoimmunity as a method to "reset" the immune system and produce a new, non-autoimmune repertoire. While the feasibility of eliminating the vast majority of mature T cells is well established, accurate and quantitative determination of the relationship of regenerated T cells to the baseline repertoire has been difficult to assess. Here, in a phase II study of HSCT for poor-prognosis multiple sclerosis, we used high-throughput deep TCRβ chain sequencing to assess millions of individual TCRs per patient sample. We found that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. In CD4+ T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process. These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T cell clones following HSCT and cellular therapies. PMID: 24531550 [PubMed - indexed for MEDLINE]
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Related Articles Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014 Oct;85(10):1116-21 Authors: Burman J, Iacobaeus E, Svenningsson A, Lycke J, Gunnarsson M, Nilsson P, Vrethem M, Fredrikson S, Martin C, Sandstedt A, Uggla B, Lenhoff S, Johansson JE, Isaksson C, Hägglund H, Carlson K, Fagius J Abstract BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. METHODS: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. RESULTS: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres. PMID: 24554104 [PubMed - indexed for MEDLINE]
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Related Articles The risk of progressive multifocal leukoencephalopathy under biological agents used in the treatment of chronic inflammatory diseases. Inflamm Allergy Drug Targets. 2014;13(2):121-7 Authors: Toussirot É, Bereau M Abstract Biological agents such as monoclonal antibodies and soluble cytokine receptors have taken on an expanding role in the treatment of chronic immune mediated diseases. Progressive multifocal leukoencephalopathy (PML) is a rare central neurological disease caused by JC virus infection that has been described in the setting of conditions with severe impairment of immune surveillance, such as haematological malignancies, stem cell or solid organ transplantation and AIDS. This serious demyelinating disease has recently been described in patients receiving monoclonal antibodies for chronic inflammatory diseases such as multiple sclerosis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus or psoriasis. We review here the disease of PML, the different biological agents used in chronic inflammatory diseases that are associated with an increased risk of PML (natalizumab, rituximab, efalizumab and alemtuzumab), and the potential mechanisms that may explain the development of PML. Based on current knowledge of the biology of the JC virus and on the mechanisms of action of these biological agents, we discuss currently available tools that may be helpful in evaluating the risk of PML in this patient population. PMID: 24559124 [PubMed - in process]
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Related Articles Transplantation of human adipose-derived stem cells enhances remyelination in lysolecithin-induced focal demyelination of rat spinal cord. Mol Biotechnol. 2014 May;56(5):470-8 Authors: Ghasemi N, Razavi S, Mardani M, Esfandiari E, Salehi H, Zarkesh Esfahani SH Abstract Adipose-derived stem cells (ADSCs) are a desirable stem cell source in neurodegenerative diseases treatment due to their ability to differentiate into different cell lineages. In this study, we transplanted human ADSCs (hADSCs) into a lysophosphatidylcholine (lysolecithin) model of multiple sclerosis (MS) and determined the efficiency of these cells in remyelination process. Forty adult rats were randomly divided into control, lysolecithin, vehicle, and transplantation groups, and focal demyelination was induced by lysolecithin injection into spinal cord. To assess motor performance, all rats were examined weekly with a standard EAE scoring scale. Four weeks after cell transplantation, to assess the extent of demyelination and remyelination, Luxol Fast Blue staining was used. In addition, immunohistochemistry technique was used for assessment of the presence of oligodendrocyte phenotype cells in damaged spinal cord. Our results indicated that hADSCs had ability to differentiate into oligodendrocyte phenotype cells and improved remyelination process. Moreover, the evaluation of rat motor functions showed that animals which were treated with hADSC compared to other groups had significant improvement (P < 0.001). Our finding showed that hADSCs transplantation for cell-based therapies may play a proper cell source in the treatment of neurodegenerative diseases such as MS. PMID: 24570177 [PubMed - indexed for MEDLINE]
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Related Articles Intranasal delivery of central nervous system-retargeted human mesenchymal stromal cells prolongs treatment efficacy of experimental autoimmune encephalomyelitis. Immunology. 2014 Jul;142(3):431-41 Authors: Fransson M, Piras E, Wang H, Burman J, Duprez I, Harris RA, LeBlanc K, Magnusson PU, Brittebo E, Loskog AS Abstract Treatment with mesenchymal stromal cells (MSCs) is currently of interest for a number of diseases including multiple sclerosis. MSCs are known to target inflamed tissues, but in a therapeutic setting their systemic administration will lead to few cells reaching the brain. We hypothesized that MSCs may target the brain upon intranasal administration and persist in central nervous system (CNS) tissue if expressing a CNS-targeting receptor. To demonstrate proof of concept, MSCs were genetically engineered to express a myelin oligodendrocyte glycoprotein-specific receptor. Engineered MSCs retained their immunosuppressive capacity, infiltrated into the brain upon intranasal cell administration, and were able to significantly reduce disease symptoms of experimental autoimmune encephalomyelitis (EAE). Mice treated with CNS-targeting MSCs were resistant to further EAE induction whereas non-targeted MSCs did not give such persistent effects. Histological analysis revealed increased brain restoration in engineered MSC-treated mice. In conclusion, MSCs can be genetically engineered to target the brain and prolong therapeutic efficacy in an EAE model. PMID: 24588452 [PubMed - indexed for MEDLINE]
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Related Articles Serum-free spheroid suspension culture maintains mesenchymal stem cell proliferation and differentiation potential. Biotechnol Prog. 2014 Jul-Aug;30(4):974-83 Authors: Alimperti S, Lei P, Wen Y, Tian J, Campbell AM, Andreadis ST Abstract There have been many clinical trials recently using ex vivo-expanded human mesenchymal stem cells (MSCs) to treat several disease states such as graft-versus-host disease, acute myocardial infarction, Crohn's disease, and multiple sclerosis. The use of MSCs for therapy is expected to become more prevalent as clinical progress is demonstrated. However, the conventional 2-dimensional (2D) culture of MSCs is laborious and limited in scale potential. The large dosage requirement for many of the MSC-based indications further exacerbates this manufacturing challenge. In contrast, expanding MSCs as spheroids does not require a cell attachment surface and is amenable to large-scale suspension cell culture techniques, such as stirred-tank bioreactors. In the present study, we developed and optimized serum-free media for culturing MSC spheroids. We used Design of Experiment (DoE)-based strategies to systematically evaluate media mixtures and a panel of different components for effects on cell proliferation. The optimization yielded two prototype serum-free media that enabled MSCs to form aggregates and proliferate in both static and dynamic cultures. MSCs from spheroid cultures exhibited the expected immunophenotype (CD73, CD90, and CD105) and demonstrated similar or enhanced differentiation potential toward all three lineages (osteogenic, chondrogenic, adipogenic) as compared with serum-containing adherent MSC cultures. Our results suggest that serum-free media for MSC spheroids may pave the way for scale-up production of MSCs in clinically relevant manufacturing platforms such as stirred tank bioreactors. PMID: 24616445 [PubMed - in process]
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Related Articles Mechanistic insights into corticosteroids in multiple sclerosis: war horse or chameleon?. Clin Neurol Neurosurg. 2014 Apr;119:6-16 Authors: Krieger S, Sorrells SF, Nickerson M, Pace TW Abstract OBJECTIVES: Relapse management is a crucial component of multiple sclerosis (MS) care. High-dose corticosteroids (CSs) are used to dampen inflammation, which is thought to hasten the recovery of MS relapse. A diversity of mechanisms drive the heterogeneous clinical response to exogenous CSs in patients with MS. Preclinical research is beginning to provide important insights into how CSs work, both in terms of intended and unintended effects. In this article we discuss cellular, systemic, and clinical characteristics that might contribute to intended and unintended CS effects when utilizing supraphysiological doses in clinical practice. The goal of this article is to consider recent insights about CS mechanisms of action in the context of MS. METHODS: We reviewed relevant preclinical and clinical studies on the desirable and undesirable effects of high-dose corticosteroids used in MS care. RESULTS: Preclinical studies reviewed suggest that corticosteroids may act in unpredictable ways in the context of autoimmune conditions. The precise timing, dosage, duration, cellular exposure, and background CS milieu likely contribute to their clinical heterogeneity. CONCLUSION: It is difficult to predict when patients will respond favorably to CSs, both in terms of therapeutic response and tolerability profile. There are specific cellular, systemic, and clinical characteristics that might merit further consideration when utilizing CSs in clinical practice, and these should be explored in a translational setting. PMID: 24635918 [PubMed - indexed for MEDLINE]
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Related Articles [Immunomodulatory properties of stem mesenchymal cells in autoimmune diseases.] Med Clin (Barc). 2014 Mar 14; Authors: Sánchez-Berná I, Santiago-Díaz C, Jiménez-Alonso J Abstract Autoimmune diseases are a cluster of disorders characterized by a failure of the immune tolerance and a hyperactivation of the immune system that leads to a chronic inflammation state and the damage of several organs. The medications currently used to treat these diseases usually consist of immunosuppressive drugs that have significant systemic toxic effects and are associated with an increased risk of opportunistic infections. Recently, several studies have demonstrated that mesenchymal stem cells have immunomodulatory properties, a feature that make them candidates to be used in the treatment of autoimmune diseases. In the present study, we reviewed the role of this therapy in the treatment of systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Crohn's disease and multiple sclerosis, as well as the potential risks associated with its use. PMID: 24636281 [PubMed - as supplied by publisher]
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Related Articles DMBA/TPA treatment is necessary for BCC formation from patched deficient epidermal cells in Ptch(flox/flox)CD4Cre(+/-) mice. J Invest Dermatol. 2014 Oct;134(10):2620-9 Authors: Uhmann A, Heß I, Frommhold A, König S, Zabel S, Nitzki F, Dittmann K, Lühder F, Christiansen H, Reifenberger J, Schulz-Schaeffer W, Hahn H Abstract The development of basal cell carcinoma (BCC), the most frequently diagnosed tumor among persons with European ancestry, is closely linked to mutations in the Hedgehog (Hh) receptor and tumor suppressor Patched1 (Ptch). Using Ptch(flox/flox)CD4Cre(+/-) mice, in which Ptch was ablated in CD4Cre-expressing cells, we demonstrate that the targeted cells can give rise to BCC after treatment with DMBA (7,12-dimethylbenz(a)anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate), but not after wounding of the skin. In addition, in this model, BCC are not caused by malfunctioning of Ptch-deficient T cells, as BCC did not develop when bone marrow (BM) of Ptch(flox/flox)CD4Cre(+/-) mice was transplanted into Ptch wild-type mice. Instead, lineage-tracing experiments and flow cytometric analyses suggest that the tumors are initiated from rare Ptch-deficient stem cell-like cells of the epidermis that express CD4. As DMBA/TPA is a prerequisite for BCC development in this model, the initiated cells need a second stimulus for expansion and tumor formation. However, in contrast to papilloma, this stimulus seems to be unrelated to alterations in the Ras signaling cascade. Together, these data suggest that biallelic loss of Ptch in CD4(+) cells does not suffice for BCC formation and that BCC formation requires a second so far unknown event, at least in the Ptch(flox/flox)CD4Cre(+/-) BCC mouse model. PMID: 24662765 [PubMed - in process]
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Related Articles The orally available, synthetic ether lipid edelfosine inhibits T cell proliferation and induces a type I interferon response. PLoS One. 2014;9(3):e91970 Authors: Abramowski P, Otto B, Martin R Abstract The drug edelfosine is a synthetic analog of 2-lysophosphatidylcholine. Edelfosine is incorporated by highly proliferating cells, e.g. activated immune cells. It acts on cellular membranes by selectively aggregating the cell death receptor Fas in membrane rafts and interference with phosphatidylcholine (PC) synthesis with subsequent induction of apoptosis. Edelfosine has been proposed for the treatment of autoimmune diseases like multiple sclerosis (MS). Earlier studies on the animal model of MS, experimental autoimmune encephalomyelitis (EAE), have generated first evidence for the efficacy of edelfosine treatment. However, it is unknown if the previously described mechanisms for edelfosine action, which are derived from in vitro studies, are solely responsible for the amelioration of EAE or if edelfosine may exert additional effects, which may be beneficial in the context of autoimmunity. Since it was the purpose of our studies to assess the potential usefulness of edelfosine for the treatment of MS, we examined its mechanism/s of action on immune functions in human T cells. Low doses of edelfosine led to a decrease in homeostatic proliferation, and further studies of the mechanism/s of action by genome-wide transcriptional profiling showed that edelfosine reduces the expression of MHC class II molecules, of molecules involved in MHC class II-associated processing and presentation, and finally upregulated a series of type I interferon-associated genes. The inhibition of homeostatic proliferation, as well as the effects on MHC class II expression and -presentation, and the induction of type I interferon-associated genes are novel and interesting in the context of developing edelfosine for clinical use in MS and possibly also other T cell-mediated autoimmune diseases. PMID: 24667731 [PubMed - in process]
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Related Articles Immunomodulatory effects of adipose-derived mesenchymal stem cells on the gene expression of major transcription factors of T cell subsets. Int Immunopharmacol. 2014 Jun;20(2):316-21 Authors: Mohammadzadeh A, Pourfathollah AA, Shahrokhi S, Hashemi SM, Moradi SL, Soleimani M Abstract It has been proposed that the immunomodulatory properties of mesenchymal stem cells (MSCs) play a crucial role in establishing and leading T lymphocytes, especially Th cell subsets, toward different functional subsets. To determine the effect of the immunomodulatory and regulatory functions of adipose-derived MSCs (AD-MSCs) on C57BL/6 spleen-isolated mononuclear cells (Spleen-MNCs), the gene expression of well-known effector and regulatory Th cell-related transcription factors, i.e., t-bet, GATA-3, Ror-γt and Foxp3, and their related cytokines, i.e., IFN-γ for Th1 cells, IL-4 for Th2 cells, IL-17 for Th17 cells and IL-10 and TGF-β for regulatory T cells, was studied using a co-culture condition system. The proliferation index of Spleen-MNCs was analyzed using a cell proliferation assay kit that utilized the CFSE staining method. Our findings indicate that AD-MSCs greatly impact the up-regulation of immunomodulatory cytokines, such as TGF-β (p<0.001), and the down-regulation of inflammatory cytokines, such as IFN-γ (p<0.005), and transcription factors, such as t-bet (p<0.001). Considering the immunomodulatory effects of MSCs in the differentiation of Th cell subsets, understanding and harnessing this property of MSCs could be a powerful strategy in the treatment of inflammatory autoimmune diseases such as multiple sclerosis. PMID: 24704622 [PubMed - in process]
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Related Articles Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system. J Exp Med. 2014 May 5;211(5):791-9 Authors: Williams JL, Patel JR, Daniels BP, Klein RS Abstract Current treatment modalities for the neurodegenerative disease multiple sclerosis (MS) use disease-modifying immunosuppressive compounds but do not promote repair. Although several potential targets that may induce myelin production have been identified, there has yet to be an approved therapy that promotes remyelination in the damaged central nervous system (CNS). Remyelination of damaged axons requires the generation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs). Although OPCs are detected in MS lesions, repair of myelin is limited, contributing to progressive clinical deterioration. In the CNS, the chemokine CXCL12 promotes remyelination via CXCR4 activation on OPCs, resulting in their differentiation into myelinating oligodendrocytes. Although the CXCL12 scavenging receptor CXCR7/ACKR3 (CXCR7) is also expressed by OPCs, its role in myelin repair in the adult CNS is unknown. We show that during cuprizone-induced demyelination, in vivo CXCR7 antagonism augmented OPC proliferation, leading to increased numbers of mature oligodendrocytes within demyelinated lesions. CXCR7-mediated effects on remyelination required CXCR4 activation, as assessed via both phospho-S339-CXCR4-specific antibodies and administration of CXCR4 antagonists. These findings identify a role for CXCR7 in OPC maturation during remyelination and are the first to use a small molecule to therapeutically enhance myelin repair in the demyelinated adult CNS. PMID: 24733828 [PubMed - indexed for MEDLINE]
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Related Articles Progress of mesenchymal stem cell therapy for neural and retinal diseases. World J Stem Cells. 2014 Apr 26;6(2):111-9 Authors: Ng TK, Fortino VR, Pelaez D, Cheung HS Abstract Complex circuitry and limited regenerative power make central nervous system (CNS) disorders the most challenging and difficult for functional repair. With elusive disease mechanisms, traditional surgical and medical interventions merely slow down the progression of the neurodegenerative diseases. However, the number of neurons still diminishes in many patients. Recently, stem cell therapy has been proposed as a viable option. Mesenchymal stem cells (MSCs), a widely-studied human adult stem cell population, have been discovered for more than 20 years. MSCs have been found all over the body and can be conveniently obtained from different accessible tissues: bone marrow, blood, and adipose and dental tissue. MSCs have high proliferative and differentiation abilities, providing an inexhaustible source of neurons and glia for cell replacement therapy. Moreover, MSCs also show neuroprotective effects without any genetic modification or reprogramming. In addition, the extraordinary immunomodulatory properties of MSCs enable autologous and heterologous transplantation. These qualities heighten the clinical applicability of MSCs when dealing with the pathologies of CNS disorders. Here, we summarize the latest progress of MSC experimental research as well as human clinical trials for neural and retinal diseases. This review article will focus on multiple sclerosis, spinal cord injury, autism, glaucoma, retinitis pigmentosa and age-related macular degeneration. PMID: 24772238 [PubMed]
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Related Articles Two-photon imaging of remyelination of spinal cord axons by engrafted neural precursor cells in a viral model of multiple sclerosis. Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):E2349-55 Authors: Greenberg ML, Weinger JG, Matheu MP, Carbajal KS, Parker I, Macklin WB, Lane TE, Cahalan MD Abstract Neural precursor cells (NPCs) offer a promising approach for treating demyelinating diseases. However, the cellular dynamics that underlie transplanted NPC-mediated remyelination have not been described. Using two-photon imaging of a newly developed ventral spinal cord preparation and a viral model of demyelination, we describe the motility and intercellular interactions of transplanted mouse NPCs expressing green fluorescent protein (GFP) with damaged axons expressing yellow fluorescent protein (YFP). Our findings reveal focal axonal degeneration that occurs in the ventral side of the spinal cord within 1 wk following intracranial instillation with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Axonal damage precedes extensive demyelination and is characterized by swelling along the length of the axon, loss of YFP signal, and transected appearance. NPCs engrafted into spinal cords of JHMV-infected mice exhibited diminished migration velocities and increased proliferation compared with transplanted cells in noninfected mice. NPCs preferentially accumulated within areas of axonal damage, initiated direct contact with axons, and subsequently expressed the myelin proteolipid protein gene, initiating remyelination. These findings indicate that NPCs transplanted into an inflammatory demyelinating microenvironment participate directly in therapeutic outcome through the wrapping of myelin around damaged neurons. PMID: 24843159 [PubMed - indexed for MEDLINE]
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Related Articles Materials for stem cell factories of the future. Nat Mater. 2014 Jun;13(6):570-9 Authors: Celiz AD, Smith JG, Langer R, Anderson DG, Winkler DA, Barrett DA, Davies MC, Young LE, Denning C, Alexander MR Abstract Polymeric substrates are being identified that could permit translation of human pluripotent stem cells from laboratory-based research to industrial-scale biomedicine. Well-defined materials are required to allow cell banking and to provide the raw material for reproducible differentiation into lineages for large-scale drug-screening programs and clinical use. Yet more than 1 billion cells for each patient are needed to replace losses during heart attack, multiple sclerosis and diabetes. Producing this number of cells is challenging, and a rethink of the current predominant cell-derived substrates is needed to provide technology that can be scaled to meet the needs of millions of patients a year. In this Review, we consider the role of materials discovery, an emerging area of materials chemistry that is in large part driven by the challenges posed by biologists to materials scientists. PMID: 24845996 [PubMed - indexed for MEDLINE]
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Related Articles Electroacupuncture Promotes the Differentiation of Transplanted Bone Marrow Mesenchymal Stem Cells Pre-Induced with Neurotrophin-3 and Retinoic Acid into Oligodendrocyte-Like Cells in Demyelinated Spinal Cord of Rats. Cell Transplant. 2014 May 22; Authors: Liu Z, He B, Zhang RY, Zhang K, Ding Y, Ruan JW, Ling EA, Wu JL, Zeng YS Abstract Transplantation of bone marrow mesenchymal stem cells (MSCs) promotes functional recovery in multiple sclerosis (MS) patients and in a murine model of MS. However, there is only a modicum of information on differentiation of grafted MSCs into oligodendrocyte-like cells in MS. The purpose of this study was to transplant neurotrophin-3 (NT-3) and retinoic acid (RA) pre-induced MSCs (NR-MSCs) into a demyelinated spinal cord induced by ethidium bromide (EB), and to investigate whether EA treatment could promote NT-3 secretion in the demyelinated spinal cord. We also sought to determine whether increased NT-3 could further enhance NR-MSCs overexpressing TrkC to differentiate into more oligodendrocyte-like cells, resulting in increased remyelination and nerve conduction in the spinal cord. Our results showed that NT-3 and RA increased transcription of the tyrosine receptor kinase C (TrkC) mRNA in cultured MSCs. EA increased NT-3 levels, and promoted differentiation of oligodendrocyte-like cells from grafted NR-MSCs in the demyelinated spinal cord. There was evidence of myelin formation by grafted NR-MSCs. In addition, NR-MSCs transplantation combined with EA treatment (the NR-MSCs+EA group) reduced demyelination and promoted remyelination. Furthermore, the conduction of cortical motor evoked potentials (MEPs) has improved as compared to controls. Together, our data suggest that pre-induced MSC transplantation combined with EA treatment not only increased MSC differentiation into oligodendrocyte-like cells forming myelin sheaths, but also promoted remyelination and functional improvement of nerve conduction in the demyelinated spinal cord. PMID: 24856958 [PubMed - as supplied by publisher]
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Related Articles Activating receptor NKG2D targets RAE-1-expressing allogeneic neural precursor cells in a viral model of multiple sclerosis. Stem Cells. 2014 Oct;32(10):2690-701 Authors: Weinger JG, Plaisted WC, Maciejewski SM, Lanier LL, Walsh CM, Lane TE Abstract Transplantation of major histocompatibility complex-mismatched mouse neural precursor cells (NPCs) into mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in rapid rejection that is mediated, in part, by T cells. However, the contribution of the innate immune response to allograft rejection in a model of viral-induced neurological disease has not been well defined. Herein, we demonstrate that the natural killer (NK) cell-expressing-activating receptor NKG2D participates in transplanted allogeneic NPC rejection in mice persistently infected with JHMV. Cultured NPCs derived from C57BL/6 (H-2(b) ) mice express the NKG2D ligand retinoic acid early precursor transcript (RAE)-1 but expression was dramatically reduced upon differentiation into either glia or neurons. RAE-1(+) NPCs were susceptible to NK cell-mediated killing whereas RAE-1(-) cells were resistant to lysis. Transplantation of C57BL/6-derived NPCs into JHMV-infected BALB/c (H-2(d) ) mice resulted in infiltration of NKG2D(+) CD49b(+) NK cells and treatment with blocking antibody specific for NKG2D increased survival of allogeneic NPCs. Furthermore, transplantation of differentiated RAE-1(-) allogeneic NPCs into JHMV-infected BALB/c mice resulted in enhanced survival, highlighting a role for the NKG2D/RAE-1 signaling axis in allograft rejection. We also demonstrate that transplantation of allogeneic NPCs into JHMV-infected mice resulted in infection of the transplanted cells suggesting that these cells may be targets for infection. Viral infection of cultured cells increased RAE-1 expression, resulting in enhanced NK cell-mediated killing through NKG2D recognition. Collectively, these results show that in a viral-induced demyelination model, NK cells contribute to rejection of allogeneic NPCs through an NKG2D signaling pathway. PMID: 24898518 [PubMed - in process]
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Related Articles Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis. Autophagy. 2014 Jul;10(7):1301-15 Authors: Dang S, Xu H, Xu C, Cai W, Li Q, Cheng Y, Jin M, Wang RX, Peng Y, Zhang Y, Wu C, He X, Wan B, Zhang Y Abstract Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e.g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4(+) T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy. PMID: 24905997 [PubMed - in process]
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Related Articles Multiple systemic transplantations of human amniotic mesenchymal stem cells exert therapeutic effects in an ALS mouse model. Cell Tissue Res. 2014 Sep;357(3):571-82 Authors: Sun H, Hou Z, Yang H, Meng M, Li P, Zou Q, Yang L, Chen Y, Chai H, Zhong H, Yang ZZ, Zhao J, Lai L, Jiang X, Xiao Z Abstract Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease involving degeneration of motor neurons in the central nervous system. Stem cell treatment is a potential therapy for this fatal disorder. The human amniotic membrane (HAM), an extremely rich and easily accessible tissue, has been proposed as an attractive material in cellular therapy and regenerative medicine because of its advantageous characteristics. In the present study, we evaluate the long-term effects of a cellular treatment by intravenous administration of human amniotic mesenchymal stem cells (hAMSCs) derived from HAM into a hSOD1(G93A) mouse model. The mice received systemic administration of hAMSCs or phosphate-buffered saline (PBS) at the onset, progression and symptomatic stages of the disease. hAMSCs were detected in the spinal cord at the final stage of the disease, in the form of isolates or clusters and were negative for β-tubulin III and GFAP. Compared with the treatment with PBS, multiple hAMSC transplantations significantly retarded disease progression, extended survival, improved motor function, prevented motor neuron loss and decreased neuroinflammation in mice. These findings demonstrate that hAMSC transplantation is a promising cellular treatment for ALS. PMID: 24906288 [PubMed - in process]
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Related Articles PET Imaging of Disease Progression and Treatment Effects in the Experimental Autoimmune Encephalomyelitis Rat Model. J Nucl Med. 2014 Jun 9;55(8):1330-1335 Authors: de Paula Faria D, Vlaming ML, Copray SC, Tielen F, Anthonijsz HJ, Sijbesma JW, Buchpiguel CA, Dierckx RA, van der Hoorn JW, de Vries EF Abstract The experimental autoimmune encephalomyelitis model is a model of multiple sclerosis that closely mimics the disease characteristics in humans. The main hallmarks of multiple sclerosis are neuroinflammation (microglia activation, monocyte invasion, and T-cell infiltration) and demyelination. PET imaging may be a useful noninvasive technique for monitoring disease progression and drug treatment efficacy in vivo. METHODS: Experimental autoimmune encephalomyelitis was induced by myelin-oligodendrocyte glycoprotein immunization in female Dark Agouti rats. Experimental autoimmune encephalomyelitis rats were imaged at baseline and at days 6, 11, 15, and 19 after immunization to monitor monocyte and microglia activation ((11)C-PK11195) and demyelination ((11)C-MeDAS) during normal disease progression and during treatment with dexamethasone. RESULTS: (11)C-PK11195 PET detected activation of microglia and monocytes in the brain stem and spinal cord during disease progression. The uptake of (11)C-PK11195 was elevated in dexamethasone-treated animals that had shown mild clinical symptoms that had resolved at the time of imaging. Demyelination was not detected by (11)C-MeDAS PET, probably because of the small size of the lesions (average, 0.13 mm). CONCLUSION: PET imaging of neuroinflammation can be used to monitor disease progression and the consequences of treatment in the experimental autoimmune encephalomyelitis rat model. PET imaging was more sensitive than clinical symptoms for detecting inflammatory changes in the central nervous system. PMID: 24914056 [PubMed - as supplied by publisher]
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Related Articles IFN-β alters neurotrophic factor expression in T cells isolated from multiple sclerosis patients - implication of novel neurotensin/NTSR1 pathway in neuroprotection. Am J Transl Res. 2014;6(3):312-9 Authors: Soltys J, Knight J, Scharf E, Pitt D, Mao-Draayer Y Abstract Inflammation in relapsing remitting multiple sclerosis (RRMS) is hypothesized to provide neuroprotective effects via altered cytokine/neurotrophin homeostasis. The distinct neurotrophin production from specific cell populations has not been systematically studied and is likely of high yield in understanding the complex regulation of MS pathogenesis. Here, we describe how the mainstream therapy interferon-β (IFN-β) modulates neurotrophin expression in T cells isolated from RRMS patients and characterize the neuroprotective capabilities of these factors. We utilize SuperArray gene screen technology to investigate the neurotrophin expression profile of T cells. We demonstrate that IFN-β induces an anti-inflammatory cytokine expression pattern in T cells. Additionally, IFN-β upregulates the expression of a novel neurotrophin receptor, the neurotensin high affinity receptor 1 (NTSR1). NTSR1 is expressed in active demyelinating lesions. Furthermore, we demonstrate that the receptor agonist neurotensin is a potent inducer of human neural stem/progenitor cell survival. Our findings highlight the importance of neurotrophin receptors in RRMS and offer insight into disease pathogenesis as well as the mechanisms of action of IFN-β. PMID: 24936223 [PubMed]
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Related Articles Current perspectives in stem cell therapy for spinal cord repair in humans: a review of work from the past 10 years. Arq Neuropsiquiatr. 2014 Jun;72(6):451-6 Authors: Mariano ED, Batista CM, Barbosa BJ, Marie SK, Teixeira MJ, Morgalla M, Tatagiba M, Li J, Lepski G Abstract UNLABELLED: Spinal cord injury (SCI) and amyotrophic laterals sclerosis (ALS) are devastating neurological conditions that affect individuals worldwide, significantly reducing quality of life, both for patients and their relatives. OBJECTIVE: The present review aims to summarize the multiple restorative approaches being developed for spinal cord repair, the use of different stem cell types and the current knowledge regarding stem cell therapy. METHOD: Review of the literature from the past 10 years of human studies using stem cell transplantation as the main therapy, with or without adjuvant therapies. CONCLUSION: The current review offers an overview of the state of the art regarding spinal cord restoration, and serves as a starting point for future studies. PMID: 24964113 [PubMed - in process]
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Related Articles Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014 Aug;20(8):954-60 Authors: Mei F, Fancy SP, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJ, Green A, Hauser SL, Chan JR Abstract Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis. PMID: 24997607 [PubMed - indexed for MEDLINE]
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Related Articles Interferon β-secreting mesenchymal stem cells combined with minocycline attenuate experimental autoimmune encephalomyelitis. J Neuroimmunol. 2014 Sep 15;274(1-2):20-7 Authors: Hou Y, Heon Ryu C, Jun JA, Kim SM, Jeong CH, Jeun SS Abstract We previously demonstrated that interferon β (IFN-β)-secreting mesenchymal stem cells (MSCs-IFN-β) strongly reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE), compared with MSCs alone. Recently, minocycline ameliorates the clinical severity of multiple sclerosis (MS). Herein, we evaluated the effects of a combined treatment of MSCs-IFN-β and minocycline on EAE mice. The combined treatment significantly alleviated the clinical severity mainly by maintaining the integrity of blood-spinal cord barrier, in a manner likely involving inhibition of microvascular disruption, matrix metalloproteinases, neuroinflammation, and enhancement of immunomodulatory effects. Therefore, this combined treatment has the potential to improve the functional recovery of patients with MS. PMID: 25005115 [PubMed - indexed for MEDLINE]
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Related Articles Autologous bone marrow transplantation for the treatment of multiple sclerosis. Curr Neurol Neurosci Rep. 2014 Sep;14(9):478 Authors: Radaelli M, Merlini A, Greco R, Sangalli F, Comi G, Ciceri F, Martino G Abstract Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and represents one of the leading causes of neurologic disability in young adults. Current treatments for MS have shown limited efficacy in patients with either a progressive or an aggressive disease course. Hematopoietic stem cell transplantation (HSCT) has been proposed to control or even cure refractory cases of MS. Indeed, HSCT is able to temporarily eradicate the autoreactive cells and to reset the aberrant immune response to self-antigens. In the last decade, owing to the growing experience in selecting the most appropriate patients to transplant and the recent advances in chemotherapeutic and support regimens, the transplant-related mortality of autologous HSCT in MS patients dropped down to 1,3 % and the progression-free survival ranges from 47 % to 100 %. Altogether, these data support autologous HSCT as a possible second-line therapy for refractory MS. PMID: 25037718 [PubMed - in process]
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Related Articles Inactive GSK3β is disturbed in the spinal cord during experimental autoimmune encephalomyelitis, but rescued by stem cell therapy. Neuroscience. 2014 Sep 26;277:498-505 Authors: Tafreshi AP, Payne N, Sun G, Sylvain A, Schulze K, Bernard C Abstract Glycogen synthase kinase 3β (GSK3β) is known to control neuroinflammation, however the status of GSK3β in multiple sclerosis, the most common inflammatory demyelinating disease of the CNS, and its animal model EAE, is unknown. In this study, we investigated the expression of phosphorylated GSK3β, the inactive form of GSK3β, in the spinal cords of EAE mice. We demonstrate that while the expression of phosphorylated GSK3β was present in radial astrocytes and neurons of the control mice that received only complete Freund's adjuvant, it was absent in radial astrocytes and significantly lower in neurons of EAE animals. The loss of phosphorylated GSK3β in radial glia and neurons in EAE spinal cords was concurrent with radial glia migration and astrogliosis. This disturbance in the expression of inactive GSK3β was recovered in neurons, but not in the radial glia, after treatment of EAE mice with adipose-derived mesenchymal stem cells capable of inducing a Th2 shift. Collectively, our results suggest a link between inactive GSK3β and modulation of the immune responses during EAE. Thus, we propose that maintenance of GSK3β in its inactive status may play a role in preserving the normal physiology of the spinal cord and amelioration of EAE following stem cell therapy. PMID: 25064057 [PubMed - in process]
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Related Articles Human ESC-derived MSCs outperform bone marrow MSCs in the treatment of an EAE model of multiple sclerosis. Stem Cell Reports. 2014 Jul 8;3(1):115-30 Authors: Wang X, Kimbrel EA, Ijichi K, Paul D, Lazorchak AS, Chu J, Kouris NA, Yavanian GJ, Lu SJ, Pachter JS, Crocker SJ, Lanza R, Xu RH Abstract Current therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stem cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS, yet the variability and low potency of MSCs from adult sources hinder their therapeutic potential. MSCs derived from human embryonic stem cells (hES-MSCs) may be better suited for clinical treatment of MS because of their unlimited and stable supply. Here, we show that hES-MSCs significantly reduce clinical symptoms and prevent neuronal demyelination in a mouse experimental autoimmune encephalitis (EAE) model of MS, and that the EAE disease-modifying effect of hES-MSCs is significantly greater than that of human bone-marrow-derived MSCs (BM-MSCs). Our evidence also suggests that increased IL-6 expression by BM-MSCs contributes to the reduced anti-EAE therapeutic activity of these cells. A distinct ability to extravasate and migrate into inflamed CNS tissues may also be associated with the robust therapeutic effects of hES-MSCs on EAE. PMID: 25068126 [PubMed - in process]
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Related Articles Women with the Alzheimer's risk marker ApoE4 lose Aβ-specific CD4⁺ T cells 10-20 years before men. Transl Psychiatry. 2014;4:e414 Authors: Begum AN, Cunha C, Sidhu H, Alkam T, Scolnick J, Rosario ER, Ethell DW Abstract Adaptive immunity to self-antigens causes autoimmune disorders, such as multiple sclerosis, psoriasis and type 1 diabetes; paradoxically, T- and B-cell responses to amyloid-β (Aβ) reduce Alzheimer's disease (AD)-associated pathology and cognitive impairment in mouse models of the disease. The manipulation of adaptive immunity has been a promising therapeutic approach for the treatment of AD, although vaccine and anti-Aβ antibody approaches have proven difficult in patients, thus far. CD4(+) T cells have a central role in regulating adaptive immune responses to antigens, and Aβ-specific CD4(+) T cells have been shown to reduce AD pathology in mouse models. As these cells may facilitate endogenous mechanisms that counter AD, an evaluation of their abundance before and during AD could provide important insights. Aβ-CD4see is a new assay developed to quantify Aβ-specific CD4(+) T cells in human blood, using dendritic cells derived from human pluripotent stem cells. In tests of >50 human subjects Aβ-CD4see showed an age-dependent decline of Aβ-specific CD4(+) T cells, which occurs earlier in women than men. In aggregate, men showed a 50% decline in these cells by the age of 70 years, but women reached the same level before the age of 60 years. Notably, women who carried the AD risk marker apolipoproteinE-ɛ4 (ApoE4) showed the earliest decline, with a precipitous drop between 45 and 52 years, when menopause typically begins. Aβ-CD4see requires a standard blood draw and provides a minimally invasive approach for assessing changes in Aβ biology that may reveal AD-related changes in physiology by a decade. Furthermore, CD4see probes can be modified to target any peptide, providing a powerful new tool to isolate antigen-specific CD4(+) T cells from human subjects. PMID: 25072319 [PubMed - in process]
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Related Articles Autologous hematopoietic stem cell transplantation in neuromyelitis optica: A registry study of the EBMT Autoimmune Diseases Working Party. Mult Scler. 2014 Jul 30; Authors: Greco R, Bondanza A, Oliveira MC, Badoglio M, Burman J, Piehl F, Hagglund H, Krasulova E, Simões BP, Carlson K, Pohlreich D, Labopin M, Saccardi R, Comi G, Mancardi GL, Bacigalupo A, Ciceri F, Farge D Abstract BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the central nervous system, hallmarked by pathogenic anti-aquaporin 4 antibodies. NMO prognosis is worse compared with multiple sclerosis. OBJECTIVE: The European Group for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) conducted a retrospective survey to analyze disease outcome following autologous stem cell transplantation (ASCT). METHODS: This retrospective multicenter study assessed the efficacy and safety of ASCT in 16 patients suffering from refractory NMO reported to the EBMT registry between 2001 and 2011. RESULTS: Fifteen patients were successfully mobilized with cyclophosphamide (Cy) and G-CSF, one with G-CSF alone. All patients received an unmanipulated autologous peripheral blood stem cell graft, after conditioning with BEAM plus anti-thymocyte globulin (ATG, n = 9 patients), thiotepa-Cy (n = 3) or Cy (200 mg/kg) plus ATG (n = 4). After a median follow-up of 47 months, three of 16 cases were progression and treatment free, while in the remaining 13 patients further treatments were administered for disability progression or relapse after ASCT. Altogether, relapse-free survival at three and five years was 31% and 10%, respectively, while progression-free survival remained 48% at three and five years. CONCLUSIONS: In these NMO patients, highly resistant to conventional treatment, ASCT allows for temporary control of the disease, despite a tendency to progress or relapse in the long term. PMID: 25078274 [PubMed - as supplied by publisher]
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Related Articles Immunomodulatory effects of the ether phospholipid edelfosine in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2014 Sep 15;274(1-2):111-24 Authors: Abramowski P, Steinbach K, Zander AR, Martin R Abstract The 2-lysophosphatidylcholine analog edelfosine induces apoptosis in highly proliferating cells, e.g. activated immune cells. We examined mechanisms of action of edelfosine on immune functions in experimental autoimmune encephalomyelitis, a well-accepted animal model for multiple sclerosis. We observed activated caspase-3 expression in lymphoid organs and the central nervous system; however, edelfosine did not induce global apoptosis. Edelfosine improved the disease course and led to reduced frequencies of CD4(+) T cells infiltrating into the central nervous system. Our data suggest edelfosine as an interesting treatment candidate for multiple sclerosis. PMID: 25086877 [PubMed - indexed for MEDLINE]
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Related Articles The role of microglia in human disease: therapeutic tool or target? Acta Neuropathol. 2014 Sep;128(3):363-80 Authors: Cartier N, Lewis CA, Zhang R, Rossi FM Abstract Microglia have long been the focus of much attention due to their strong proliferative response (microgliosis) to essentially any kind of damage to the CNS. More recently, we reached the realization that these cells play specific roles in determining progression and outcomes of essentially all CNS disease. Thus, microglia has ceased to be viewed as an accessory to underlying pathologies and has now taken center stage as a therapeutic target. Here, we review how our understanding of microglia's involvement in promoting or limiting the pathogenesis of diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, multiple sclerosis, X-linked adrenoleukodystrophy (X-ALD) and lysosomal storage diseases (LSD) has changed over time. While strategies to suppress the deleterious and promote the virtuous functions of microglia will undoubtedly be forthcoming, replacement of these cells has already proven its usefulness in a clinical setting. Over the past few years, we have reached the realization that microglia have a developmental origin that is distinct from that of bone marrow-derived myelomonocytic cells. Nevertheless, microglia can be replaced, in specific situations, by the progeny of hematopoietic stem cells (HSCs), pointing to a strategy to engineer the CNS environment through the transplantation of modified HSCs. Thus, microglia replacement has been successfully exploited to deliver therapeutics to the CNS in human diseases such as X-ALD and LSD. With this outlook in mind, we will discuss the evidence existing so far for microglial involvement in the pathogenesis and the therapy of specific CNS disease. PMID: 25107477 [PubMed - in process]
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Related Articles Autologous haematopoietic stem cell transplantation reduces abnormalities in the expression of immune genes in multiple sclerosis. Clin Sci (Lond). 2015 Jan;128(2):111-20 Authors: de Paula A Sousa A, Malmegrim KC, Panepucci RA, Brum DS, Barreira AA, Carlos Dos Santos A, Araújo AG, Covas DT, Oliveira MC, Moraes DA, Pieroni F, Barros GM, Simões BP, Nicholas R, Burt RK, Voltarelli JC, Muraro PA Abstract Autologous haematopoietic stem-cell transplantation (AHSCT) has been experimented as a treatment in patients affected by severe forms of multiple sclerosis (MS) who failed to respond to standard immunotherapy. The rationale of AHSCT is to 'reboot' the immune system and reconstitute a new adaptive immunity. The aim of our study was to identify, through a robust and unbiased transcriptomic analysis, any changes of gene expression in T-cells potentially underlying the treatment effect in patients who underwent non-myeloablative AHSCT for treatment of MS. We evaluated by microarray DNA-chip technology the gene expression of peripheral CD4+ and CD8+ T-cell subsets sorted from patients with MS patients before AHSCT, at 6 months, 1 year and 2 years after AHSCT and from healthy control subjects. Hierarchical clustering analysis revealed that reconstituted CD8+ T-cells of MS patients at 2 years post-transplantation, aggregated together with healthy controls, suggesting a normalization of gene expression in CD8+ cells post-therapy. When we compared the gene expression in MS patients before and after therapy, we detected a large number of differentially expressed genes (DEG) in both CD8+ and CD4+ T-cell subsets at all time points after transplantation. We catalogued the biological function of DEG and we selected 27 genes known to be involved in immune function for accurate quantification of gene expression by real-time PCR. The analysis confirmed and extended with quantitative data, a number of significant changes in both the CD4+ and CD8+ T-cells subsets from MS post-transplant. Notably, CD8+ T-cells revealed more extensive changes in the expression of genes involved in effector immune responses. PMID: 25116724 [PubMed - indexed for MEDLINE]
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Related Articles Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders. Front Cell Neurosci. 2014;8:203 Authors: Irwin RW, Solinsky CM, Brinton RD Abstract Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer's disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer's pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer's mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer's, Parkinson's, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer's disease (AD) that have the potential to accelerate therapeutic translation for multiple unmet neurological needs. PMID: 25126056 [PubMed]
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Related Articles Designer's microglia with novel delivery system in neurodegenerative diseases. Med Hypotheses. 2014 Oct;83(4):510-2 Authors: Baig AM Abstract Neurodegenerative diseases are a group of central nervous system diseases that have a high rate of morbidity and mortality. More disabling than lethal, the pathogenesis of many of these diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Multiple sclerosis, (MS) remains to be established. Even after passage of several decades subsequent to their first recognition, these diseases have proven to be notoriously refractory towards drug treatment. Stem cell therapy itself has faced problems like ethical issues with such transplants, difficult and risky implantation routes and immune rejections of the implanted stem cells. Somatic cell nuclear transfer (SCNT) offers a hope to the aforesaid diseases if the cells selected for nuclear donation itself has inherent regenerative and scavenging properties. Here we propose olfactory ensheathing cells (OEC's) as the donor somatic cell that conceivably would attempt regeneration in above mentioned diseases by differentiating into glia, which would have healthy mitochondria and without any fear of immune rejection. Also proposed is a method of delivering these cells after SCNT to the brain by a novel "transcribrial route" through a device that can deliver cells to the brain across the cribriform plate of ethmoid bone. PMID: 25146247 [PubMed - in process]
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Related Articles Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats. Neurobiol Dis. 2014 Nov;71:220-33 Authors: Castelo-Branco G, Stridh P, Guerreiro-Cacais AO, Adzemovic MZ, Falcão AM, Marta M, Berglund R, Gillett A, Hamza KH, Lassmann H, Hermanson O, Jagodic M Abstract Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS) in young adults. Chronic treatments with histone deacetylase inhibitors (HDACis) have been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, by targeting immune responses. We have recently shown that the HDAC inhibition/knockdown in the presence of thyroid hormone (T3) can also promote oligodendrocyte (OL) differentiation and expression of myelin genes in neural stem cells (NSCs) and oligodendrocyte precursors (OPCs). In this study, we found that treatment with an HDACi, valproic acid (VPA), and T3, alone or in combination, directly affects encephalitogenic CD4+ T cells. VPA, but not T3, compromised their proliferation, while both molecules reduced the frequency of IL-17-producing cells. Transfer of T3, VPA and VPA/T3 treated encephalitogenic CD4+ T cells into naïve rats induced less severe EAE, indicating that the effects of these molecules are persistent and do not require their maintenance after the initial stimuli. Thus, we investigated the effect of acute treatment with VPA and l-thyroxine (T4), a precursor of T3, on myelin oligodendrocyte glycoprotein-induced EAE in Dark Agouti rats, a close mimic of MS. We found that a brief treatment after disease onset led to sustained amelioration of EAE and prevention of inflammatory demyelination in the CNS accompanied with a higher expression of myelin-related genes in the brain. Furthermore, the treatment modulated immune responses, reduced the number of CD4+ T cells and affected the Th1 differentiation program in the brain. Our data indicate that an acute treatment with VPA and T4 after the onset of EAE can produce persistent clinically relevant therapeutic effects by limiting the pathogenic immune reactions while promoting myelin gene expression. PMID: 25149263 [PubMed - in process]
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Related Articles Pharmacological intervention at CCR1 and CCR5 as an approach for cancer: help or hindrance. Curr Top Med Chem. 2014;14(13):1553-73 Authors: Karash A, Mazzoni MR, Gilchrist A Abstract While a number of agents directed at chemokine receptors have entered clinic trials, the vast majority of these have failed, and the enthusiasm for this class of drugs has been attenuated. To date, there are two drugs that inhibit chemokine receptors approved by the FDA. The first to be approved in 2007 was maraviroc (brand name Selzentry, or Celsentri outside the US) which targets CCR5 and is used for the treatment of HIV infection. The second is plerixafor (Mozobil) which was approved in 2008, targets CXCR4, and is used for the mobilization of hematopoietic stem cells. This review will focus on the CC chemokine receptors CCR1 and CCR5. These G protein coupled receptors are both activated by a relatively large number of chemokines, most of which overlap. While most of the drugs for CCR1 have been assessed in the context of autoimmune diseases like multiple sclerosis and rheumatoid arthritis, and those for CCR5 were examined for HIV-infection, we review the role of these receptors in relation to cancer. Recently introduced pharmacophores that serve as agonists or antagonists for the receptors are presented. Efforts to exploit polypharmacology approaches using promiscuous compounds that target more than one receptor are also considered. PMID: 25159162 [PubMed - in process]
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Related Articles New directions for rabbit antithymocyte globulin (Thymoglobulin(®)) in solid organ transplants, stem cell transplants and autoimmunity. Drugs. 2014 Sep;74(14):1605-34 Authors: Mohty M, Bacigalupo A, Saliba F, Zuckermann A, Morelon E, Lebranchu Y Abstract In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin(®) was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn's disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future. PMID: 25164240 [PubMed - in process]
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Related Articles Mesenchymal stem cell-based therapy in a mouse model of experimental autoimmune encephalomyelitis (EAE). Methods Mol Biol. 2014;1213:303-19 Authors: Bowles AC, Scruggs BA, Bunnell BA Abstract Multiple sclerosis (MS) is a common neurodegenerative disease that presents after an auto-reactive immune response against constituents of the central nervous system. Demyelination, inflammation, and white matter lesions are all hallmarks of this disease. Clinical research supports the use of mesenchymal stem cells (MSCs) as therapy for MS to ameliorate symptoms and pathology. MSCs can be isolated from multiple tissues, including adipose and bone marrow, and are able to migrate to sites of pathology, release anti-inflammatory factors, and provide immunomodulatory and neuroprotective effects once administered. Numerous studies have demonstrated the beneficial effects of MSCs in experimental autoimmune encephalomyelitis (EAE), an induced model of MS. EAE can be induced in several species; however, the mouse is commonly used for therapeutic testing. In the following chapter, scientists will be able to learn how to prepare reagents and MSCs (e.g., isolate, culture, and expand) as well as skillfully execute induction of EAE in mice and administer stem cell-based treatments. Standard methods used to evaluate the disease progression and analyze postmortem tissues are also included. PMID: 25173393 [PubMed - in process]
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Related Articles A truncation variant of the cation channel P2RX5 is upregulated during T cell activation. PLoS One. 2014;9(9):e104692 Authors: Abramowski P, Ogrodowczyk C, Martin R, Pongs O Abstract Members of the P2X family of ligand-gated cation channels (P2RX) are expressed by various cell types including neurons, smooth- and cardiac muscle cells, and leukocytes. The channels mediate signalling in response to extracellular ATP. Seven subunit isoforms (P2RX1-P2RX7) have been identified and these can assemble as homo- and heterotrimeric molecules. In humans, P2RX5 exists as a natural deletion mutant lacking amino acids 328-349 of exon 10, which are part of transmembrane (TM) 2 and pre-TM2 regions in other organisms like rat, chicken and zebrafish. We show that P2RX5 gene expression of human T lymphocytes is upregulated during activation. P2RX5 is recruited to the cell surface. P2RX5-siRNA-transfected CD4+ T cells produced twofold more IL-10 than controls. Surface and intracellular P2RX5 expression was upregulated in activated antigen-specific CD4+ T cell clones. These data indicate a functional role of the human P2RX5 splice variant in T cell activation and immunoregulation. PMID: 25181038 [PubMed - in process]
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Related Articles Regionally-specified second trimester fetal neural stem cells reveals differential neurogenic programming. PLoS One. 2014;9(9):e105985 Authors: Fan Y, Marcy G, Lee ES, Rozen S, Mattar CN, Waddington SN, Goh EL, Choolani M, Chan JK Abstract Neural stem/progenitor cells (NSC) have the potential for treatment of a wide range of neurological diseases such as Parkinson Disease and multiple sclerosis. Currently, NSC have been isolated only from hippocampus and subventricular zone (SVZ) of the adult brain. It is not known whether NSC can be found in all parts of the developing mid-trimester central nervous system (CNS) when the brain undergoes massive transformation and growth. Multipotent NSC from the mid-trimester cerebra, thalamus, SVZ, hippocampus, thalamus, cerebellum, brain stem and spinal cord can be derived and propagated as clonal neurospheres with increasing frequencies with increasing gestations. These NSC can undergo multi-lineage differentiation both in vitro and in vivo, and engraft in a developmental murine model. Regionally-derived NSC are phenotypically distinct, with hippocampal NSC having a significantly higher neurogenic potential (53.6%) over other sources (range of 0%-27.5%, p<0.004). Whole genome expression analysis showed differential gene expression between these regionally-derived NSC, which involved the Notch, epidermal growth factor as well as interleukin pathways. We have shown the presence of phenotypically-distinct regionally-derived NSC from the mid-trimester CNS, which may reflect the ontological differences occurring within the CNS. Aside from informing on the role of such cells during fetal growth, they may be useful for different cellular therapy applications. PMID: 25181041 [PubMed - in process]
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Related Articles Ontogeny and functions of central nervous system macrophages. J Immunol. 2014 Sep 15;193(6):2615-21 Authors: Katsumoto A, Lu H, Miranda AS, Ransohoff RM Abstract Microglia, the only nonneuroepithelial cells found in the parenchyma of the CNS, originate during embryogenesis from the yolk sac and enter the CNS quite early (embryonic day 9.5-10 in mice). Thereafter, microglia are maintained independently of any input from the blood and, in particular, do not require hematopoietic stem cells as a source of replacement for senescent cells. Monocytes are hematopoietic cells, derived from bone marrow. The ontogeny of microglia and monocytes is important for understanding CNS pathologies. Microglial functions are distinct from those of blood-derived monocytes, which invade the CNS only under pathological conditions. Recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions. In this article, we discuss the physiology of microglia and the functions of monocytes in CNS pathology. We address the roles of microglia and monocytes in neurodegenerative diseases as an example of CNS pathology. PMID: 25193935 [PubMed - indexed for MEDLINE]
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Related Articles The non-cell-autonomous component of ALS: new in vitro models and future challenges. Biochem Soc Trans. 2014 Oct;42(5):1270-4 Authors: Ferraiuolo L Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the motor nerves. At present, there is no effective therapy for this devastating disease and only one Food and Drug Administration (FDA)-approved drug, riluzole, is known to moderately extend survival. In the last decade, the field of ALS has made a remarkable leap forward in understanding some of the genetic causes of this disease and the role that different cell types play in the degenerative mechanism affecting motor neurons. In particular, astrocytes have been implicated in disease progression, and multiple studies suggest that these cells are valuable therapeutic targets. Recent technological advancements have provided new tools to generate astrocytes from ALS patients either from post-mortem biopsies or from skin fibroblasts through genetic reprogramming. The advent of induced pluripotent stem cell (iPSC) technology and the newly developed induced neural progenitor cells (iNPCs) have created unprecedented exciting opportunities to unravel the mechanisms involved in neurodegeneration and initiate high-throughput drug screenings. PMID: 25233402 [PubMed - in process]
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Related Articles Mesenchymal stem cells: potential in treatment of neurodegenerative diseases. Curr Stem Cell Res Ther. 2014;9(6):513-21 Authors: Tanna T, Sachan V Abstract Mesenchymal Stem Cells or Marrow Stromal Cells (MSCs) have long been viewed as a potent tool for regenerative cell therapy. MSCs are easily accessible from both healthy donor and patient tissue and expandable in vitro on a therapeutic scale without posing significant ethical or procedural problems. MSC based therapies have proven to be effective in preclinical studies for graft versus host disease, stroke, myocardial infarction, pulmonary fibrosis, autoimmune disorders and many other conditions and are currently undergoing clinical trials at a number of centers all over the world. MSCs are also being extensively researched as a therapeutic tool against neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS). MSCs have been discussed with regard to two aspects in the context of neurodegenerative diseases: their ability to transdifferentiate into neural cells under specific conditions and their neuroprotective and immunomodulatory effects. When transplanted into the brain, MSCs produce neurotrophic and growth factors that protect and induce regeneration of damaged tissue. Additionally, MSCs have also been explored as gene delivery vehicles, for example being genetically engineered to over express glial-derived or brain-derived neurotrophic factor in the brain. Clinical trials involving MSCs are currently underway for MS, ALS, traumatic brain injuries, spinal cord injuries and stroke. In the present review, we explore the potential that MSCs hold with regard to the aforementioned neurodegenerative diseases and the current scenario with reference to the same. PMID: 25248677 [PubMed - in process]
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Related Articles Immune surveillance of the central nervous system in multiple sclerosis - Relevance for therapy and experimental models. J Neuroimmunol. 2014 Nov 15;276(1-2):9-17 Authors: Hussain RZ, Hayardeny L, Cravens PC, Yarovinsky F, Eagar TN, Arellano B, Deason K, Castro-Rojas C, Stüve O Abstract Treatment of central nervous system (CNS) autoimmune disorders frequently involves the reduction, or depletion of immune-competent cells. Alternatively, immune cells are being sequestered away from the target organ by interfering with their movement from secondary lymphoid organs, or their migration into tissues. These therapeutic strategies have been successful in multiple sclerosis (MS), the most prevalent autoimmune inflammatory disorder of the CNS. However, many of the agents that are currently approved or in clinical development also have severe potential adverse effects that stem from the very mechanisms that mediate their beneficial effects by interfering with CNS immune surveillance. This review will outline the main cellular components of the innate and adaptive immune system that participate in host defense and maintain immune surveillance of the CNS. Their pathogenic role in MS and its animal model experimental autoimmune encephalomyelitis (EAE) is also discussed. Furthermore, an experimental model is introduced that may assist in evaluating the effect of therapeutic interventions on leukocyte homeostasis and function within the CNS. This model or similar models may become a useful tool in the repertoire of pre-clinical tests of pharmacological agents to better explore their potential for adverse events. PMID: 25282087 [PubMed - as supplied by publisher]
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Related Articles NAD+ protects against EAE by regulating CD4+ T-cell differentiation. Nat Commun. 2014;5:5101 Authors: Tullius SG, Biefer HR, Li S, Trachtenberg AJ, Edtinger K, Quante M, Krenzien F, Uehara H, Yang X, Kissick HT, Kuo WP, Ghiran I, de la Fuente MA, Arredouani MS, Camacho V, Tigges JC, Toxavidis V, El Fatimy R, Smith BD, Vasudevan A, ElKhal A Abstract CD4(+) T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD(+)) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4(+)IFNγ(+)IL-10(+) T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD(+) regulates CD4(+) T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD(+), the frequency of T-bet(-/-) CD4(+)IFNγ(+) T cells was twofold higher than wild-type CD4(+) T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4(+) T-cell differentiation and demonstrate that NAD(+) may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases. PMID: 25290058 [PubMed - in process]
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Related Articles Human Wharton?s jelly-derived stem cells display immunomodulatory properties and transiently improve rat experimental autoimmune encephalomyelitis. Cell Transplant. 2014 Oct 10; Authors: Donders R, Vanheusden M, Bogie JF, Ravanidis S, Thewissen K, Stinissen P, Gyselaers W, Hendriks JJ, Hellings N Abstract Umbilical cord matrix or Wharton?s jelly-derived stromal cells (WJ-MSCs) are an easily accessible source of mesenchymal-like stem cells. Recent studies describe a hypo-immunogenic phenotype, multipotent differentiation potential and trophic support function for WJ-MSCs, with variable clinical benefit in degenerative disease models such as stroke, myocardial infarction and Parkinson?s disease. It remains unclear whether WJ-MSCs have therapeutic value for multiple sclerosis (MS), where autoimmune-mediated demyelination and neurodegeneration need to be halted. In this study, we investigated whether WJ-MSCs possess the required properties to effectively and durably reverse these pathological hallmarks, and whether they survive in an inflammatory environment after transplantation. WJ-MSCs displayed a lowly immunogenic phenotype and showed intrinsic expression of neurotrophic factors and a variety of anti-inflammatory molecules. Furthermore, they dose-dependently suppressed proliferation of activated T cells using contact-dependent and paracrine mechanisms. Indoleamine 2,3-dioxygenase 1 was identified as one of the main effector molecules responsible for the observed T cell suppression. The immune-modulatory phenotype of WJ-MSCs was further enhanced after pro-inflammatory cytokine treatment in vitro (licensing). In addition to their effect on adaptive immunity, WJ-MSCs interfered with dendritic cell differentiation and maturation, thus directly affecting antigen presentation and therefore T cell priming. Systemically infused WJ-MSCs potently but transiently ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model for MS, when injected at onset or during chronic disease. This protective effect was paralleled with a reduction in autoantigen-induced T cell proliferation, confirming their immune-modulatory activity in vivo. Surprisingly, in vitro licensed WJ-MSCs did not ameliorate EAE, indicative of a fast rejection as a result of enhanced immunogenicity. Collectively, we show that WJ-MSCs have trophic support properties and effectively modulate immune cell functioning both in vitro and in the EAE model, suggesting WJ-MSC may hold promise for MS therapy. Future research is needed to optimize survival of stem cells and enhance clinical durability. PMID: 25310756 [PubMed - as supplied by publisher]
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Related Articles Stem cell transplantation in neurological diseases: improving effectiveness in animal models. Front Cell Dev Biol. 2014;2:17 Authors: Adami R, Scesa G, Bottai D Abstract Neurological diseases afflict a growing proportion of the human population. There are two reasons for this: first, the average age of the population (especially in the industrialized world) is increasing, and second, the diagnostic tools to detect these pathologies are now more sophisticated and can be used on a higher percentage of the population. In many cases, neurological disease has a pharmacological treatment which, as in the case of Alzheimer's disease, Parkinson's disease, Epilepsy, and Multiple Sclerosis can reduce the symptoms and slow down the course of the disease but cannot reverse its effects or heal the patient. In the last two decades the transplantation approach, by means of stem cells of different origin, has been suggested for the treatment of neurological diseases. The choice of slightly different animal models and the differences in methods of stem cell preparation make it difficult to compare the results of transplantation experiments. Moreover, the translation of these results into clinical trials with human subjects is difficult and has so far met with little success. This review seeks to discuss the reasons for these difficulties by considering the differences between human and animal cells (including isolation, handling and transplantation) and between the human disease model and the animal disease model. PMID: 25364724 [PubMed]
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Related Articles Cell-based therapy approaches: the hope for incurable diseases. Regen Med. 2014 Sep;9(5):649-72 Authors: Buzhor E, Leshansky L, Blumenthal J, Barash H, Warshawsky D, Mazor Y, Shtrichman R Abstract Cell therapies aim to repair the mechanisms underlying disease initiation and progression, achieved through trophic effect or by cell replacement. Multiple cell types can be utilized in such therapies, including stem, progenitor or primary cells. This review covers the current state of cell therapies designed for the prominent disorders, including cardiovascular, neurological (Parkinson's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury), autoimmune (Type 1 diabetes, multiple sclerosis, Crohn's disease), ophthalmologic, renal, liver and skeletal (osteoarthritis) diseases. Various cell therapies have reached advanced clinical trial phases with potential marketing approvals in the near future, many of which are based on mesenchymal stem cells. Advances in pluripotent stem cell research hold great promise for regenerative medicine. The information presented in this review is based on the analysis of the cell therapy collection detailed in LifeMap Discovery(®) (LifeMap Sciences Inc., USA) the database of embryonic development, stem cell research and regenerative medicine. PMID: 25372080 [PubMed - in process]
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Related Articles The potential of human umbilical cord-derived mesenchymal stem cells as a novel cellular therapy for multiple sclerosis. Cell Transplant. 2014 Nov 5; Authors: Li JF, Zhang DJ, Geng T, Chen L, Huang H, Yin HL, Zhang YZ, Lou JY, Cao B, Wang YL Abstract Multiple sclerosis (MS) is a complex disease of neurological disability, affecting more than 300 out of every one million people in the world. The purpose of the study was to evaluate the therapeutic effects of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation in MS patients. Twenty-three patients were enrolled in this study and 13 of them were given hUC-MSC therapy at the same time as anti-inflammatory treatment, whereas the control patients received the anti-inflammatory treatment only. Treatment schedule included 1,000 mg/kg of methylprednisolone i.v. daily for 3 days and then 500 mg/kg for 2 days, followed by oral prednisone 1mg/kg/day for 10 days. The dosage of prednisone was then reduced by 5mg every two weeks until reaching a 5mg/day maintenance dosage. Intravenous infusion of hUC-MSCs was applied three times in a 6 week period for each patient. The overall symptoms of the hUC-MSC treated patients improved compared to patients in the control group. Both the EDSS scores and relapse occurrence were significantly lower than those of the control patients. Inflammatory cytokines were assessed, and the data demonstrated a shift from Th1 to Th2 immunity in hUC-MSC treated patients. Our data demonstrated a high potential for hUC-MSC treatment of MS. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation. PMID: 25385295 [PubMed - as supplied by publisher]
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Related Articles Current role of chemotherapy and bone marrow transplantation in multiple sclerosis. Curr Treat Options Neurol. 2015 Jan;17(1):324 Authors: Sola-Valls N, Sepúlveda M, Blanco Y, Saiz A Abstract OPINION STATEMENT: The range of available treatment options for patients with multiple sclerosis (MS) has expanded tremendously in recent years, adding further complexity to the therapeutic decision-making process. The first-generation therapies interferon beta and glatiramer acetate have been safely used for more than 20 years, but are only partially effective. Many of the newly approved MS therapies such as oral agents and monoclonal antibodies are selective immunosuppressants that appear to have improved efficacy and/or are more convenient, albeit in the absence of a long-term safety record. Although some are known to be associated with serious adverse effects, these treatments provide evidence-based therapeutic options for patients with suboptimal response or breakthrough disease. In this new scenario, non-selective immunosuppressive drugs and autologous hematopoietic stem cell transplantation are still present but likely play a more limited role than before. In this review, we briefly summarize the current, recent, and most imminent immunosuppressive therapies, and present an overall summary along with a discussion of their role in the current MS treatment scenario. PMID: 25398465 [PubMed]
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Related Articles Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy. World J Stem Cells. 2014 Nov 26;6(5):526-39 Authors: Glenn JD, Whartenby KA Abstract Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses. PMID: 25426250 [PubMed]
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Related Articles Generating induced pluripotent stem cells for multiple sclerosis therapy. Regen Med. 2014 Nov;9(6):709-11 Authors: Fossati V, Douvaras P PMID: 25431906 [PubMed - in process]
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Related Articles Fluoxetin upregulates connexin 43 expression in astrocyte. Basic Clin Neurosci. 2014;5(1):74-9 Authors: Mostafavi H, Khaksarian M, Joghataei MT, Hassanzadeh G, Soleimani M, Eftekhari S, Soleimani M, Mousavizadeh K, Hadjighassem MR Abstract INTRODUCTION: Recent studies have shown that astrocytes play major roles in normal and disease condition of the central nervous system including multiple sclerosis (MS). Molecular target therapy studies in MS have revealed that connexin-43 (Cx43) and Aquaporin-4 (AQP4) contents of astrocytes undergo expression alteration. Fluoxetine had some effects in MS patients unrelated to its known antidepressant effects. Some of fluoxetine effects were attributed to its capability of cAMP signaling pathway stimulation. This study aimed to investigate possible acute effects of fluoxetine on Cx43 and AQP4 expression in astrocyte. METHODS: Astrocytoma cells were treated for 24 hours with fluoxetine (10 and 20 µg/ml) with or without adenyl cyclase (AC) and protein kinase A (PKA) inhibition. Cx43 expression at both mRNA and protein levels and AQP4 expression at mRNA level were evaluated. RESULTS: Acquired results showed that fluoxetine with and without AC and PKA inhibition resulted in Cx43 up-regulation both in mRNA and protein levels, whereas AQP4 expression have not changed. DISCUSSION: In conclusion, data showed that fluoxetine alone and in the absence of serotonin acutely up-regulated Cx43 expression in astrocytes that can be assumed in molecular target therapy of MS patients. It seems that cAMP involvement in fluoxetine effects need more researches. PMID: 25436087 [PubMed]
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Related Articles Randomized Placebo-Controlled Phase II Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis. PLoS One. 2014;9(12):e113936 Authors: Llufriu S, Sepúlveda M, Blanco Y, Marín P, Moreno B, Berenguer J, Gabilondo I, Martínez-Heras E, Sola-Valls N, Arnaiz JA, Andreu EJ, Fernández B, Bullich S, Sánchez-Dalmau B, Graus F, Villoslada P, Saiz A Abstract OBJECTIVE: Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study. METHODS: Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×106 bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects. RESULTS: At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (-2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients. CONCLUSION: Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266. PMID: 25436769 [PubMed - in process]
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Related Articles Identification of nucleoside analogues as inducers of neuronal differentiation in a human reporter cell line and adult stem cells. Chem Biol Drug Des. 2014 Dec 2; Authors: Raasch K, Malecki E, Siemann M, Martinez MM, Heinisch JJ, Müller J, Bakota L, Kaltschmidt C, Kaltschmidt B, Rosemeyer H, Brandt R Abstract Nucleoside analogues (NSAs) were among the first chemotherapeutic agents and could also be useful for manipulation of cell fate. To investigate the potential of NSAs for induction of neuronal differentiation, we developed a novel phenotypic assay based on a human neuron-committed teratocarcinoma cell line (NT2) as a model for neuronal progenitors and constructed a NT2-based reporter cell line that expressed eGFP under the control of a neuron-specific promoter. We tested 38 structurally related NSAs and determined their activity to induce neuronal differentiation by immunocytochemistry of neuronal marker proteins, live cell imaging, fluorometric detection and immunoblot analysis. We identified twelve NSAs, which induced neuronal differentiation to different extents. NSAs with highest activity carried a halogen substituent at their pyrimidine nucleobase and an unmodified or 2'-O-methyl substituted 2-deoxy-ß-D-ribofuranosyl residue as glyconic moiety. Cladribine, a purine nucleoside with similar structural features and in use to treat leukemia and multiple sclerosis, induced also differentiation of adult human neural crest-derived stem cells. Our results suggest that NSAs could be useful for manipulation of neuronal cell fate in cell replacement therapy or treatment of neurodegenerative disorders. The data on the structure and function relationship will help to design compounds with increased activity and low toxicity. This article is protected by copyright. All rights reserved. PMID: 25444247 [PubMed - as supplied by publisher]
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Related Articles Stem cell tourism - A web-based analysis of clinical services available to international travellers. Travel Med Infect Dis. 2014 Oct 7;12(6PB):695-701 Authors: Connolly R, O'Brien T, Flaherty G Abstract BACKGROUND: Stem cell therapies are advertised through online resources which describe a range of treatments with diverse clinical indications. Stem cell tourists may not be aware of the information they should seek when consulting these clinics, or of the potential risks involved. The aim of this study was to characterise the therapies offered by online stem cell clinics. METHODS: A web based search utilising five search terms was employed. The first twenty pages of each search result were screened against 340 variables. RESULTS: 224 out of 1091 websites advertised stem cell clinics. 68 eligible sites covering 21 countries were evaluated. The top five clinical indications for stem cell therapy were multiple sclerosis, anti-ageing, Parkinson's disease, stroke and spinal cord injury. Adult, autologous stem cells were the most commonly utilised stem cell, and these were frequently sourced from bone marrow and adipose tissue and administered intravenously. Thirty-four per cent of sites mentioned the number of patients treated while one quarter of clinics provided outcome data. Twenty-nine per cent of clinics had an internationally recognised accreditation. Fifteen per cent of clinics stated that their therapies posed no risk. Eighty-eight per cent of clinics claimed treatment effectiveness, with 16% describing their curative potential. Over 40% of sites did not specify the number or duration of treatments. Fifty-three per cent of clinics requested access to patients' medical records, and 12% recommended patients discuss the proposed therapy with their doctor. No clinic recommended that travellers consult a travel medicine specialist or receive vaccinations prior to their intended travel. One quarter of sites discussed contraindications to treatment, with 41% of sites detailing follow up patient care. CONCLUSIONS: There is potential for stem cell tourists to receive misleading or deficient information from online stem cell clinics. Both the stem cell tourist and travel medicine practitioner should be educated on the potential risks associated with stem cell clinical services advertised online. PMID: 25449045 [PubMed - as supplied by publisher]
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Related Articles Increased CXCL10 expression in MS MSCs and monocytes is unaffected by AHSCT. Ann Clin Transl Neurol. 2014 Sep;1(9):650-8 Authors: Bonechi E, Aldinucci A, Mazzanti B, di Gioia M, Repice AM, Manuelli C, Saccardi R, Massacesi L, Ballerini C Abstract OBJECTIVE: To confirm CXCL10 over production in bone marrow mesenchymal stem cells (MSCs) and circulating monocytes isolated from multiple sclerosis patients (MS) and identify predate cell molecular signature; to extend this analysis after autologous hematopoietic stem cell transplantation (AHSCT) to test if therapy has modifying effects on MSCs and circulating monocytes. METHODS: MSCs and monocytes were isolated from 19 MS patients who undergone AHSCT before and seven of them at least 3 years after transplant. CXCL10 production was detected after LPS/IFN-γ stimulation. TLR4 signaling pathways were investigated by means of transcription factors phosphorylation/activation level. RT-PCR of activated transcription factors was performed to quantify their expression. All experiments were conducted in parallel with 24 matched healthy donors (HD). RESULTS: CXCL10 expression was significantly increased in both peripheral circulating monocytes and BM MSCs compared to HD. We showed that CXCL10 production is determined by an altered signaling pathway downstream TLR4, with the involvement of STAT-1, NF-κB, p38, JNK, and CREB. All upregulated transcription factors are more phosphorylated in MS patient sample. These features are not modified after AHSCT. INTERPRETATION: We demonstrated that in MS two different cell lineages are characterized by significantly increased production of CXCL10, due to altered signaling pathways of innate immune reaction mediated by TLR4, probably associated with disease phenotype. This characteristic is not modified by AHSCT, suggesting that when T and B lymphocytes are reset, other possible components of MS pathology, such as CXCL10 over production, do not determine therapy outcome. PMID: 25493279 [PubMed]
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Mesenchymal properties of SJL mice-stem cells and their efficacy as autologous therapy in relapsing-remitting multiple sclerosis model. Stem Cell Res Ther. 2014 Dec 12;5(6):134 Authors: Marin-Bañasco C, Suardíaz García M, Hurtado Guerrero I, Maldonado Sánchez R, Estivill-Torrús G, Leyva Fernández L, Fernández Fernández O Abstract INTRODUCTION: Mesenchymal stem cells (MSCs) are a multipotent population of adult stem cells, which may represent a promising therapeutic approach for neurological autoimmune diseases such as multiple sclerosis. The mouse is the most used species for obtaining and studying the characteristics of MSC and their potential as autologous transplants in pre-clinical models. However, conflicting data have been published disclosing intraspecies variations. The choice of the mouse strain and the tissue source appear, among others, as important factors in the experimental application of MSCs. METHODS: Adipose tissue-derived MSCs obtained from the SJL/JCrl mouse strain (SJL-AdMSC) have been cultured for a long time (from passage 0 up to 15) under controlled experimental conditions, and their growth rate, morphology, stromal and haematopoietic marker expression profiles and differentiation capacity towards adipocytes, osteocytes and chondrocytes have been determined. Moreover, their preclinical efficacy has been assessed by autologous transplant in relapsing-remitting experimental autoimmune encephalomielitis (RR-EAE)-induced SJL mice (a well established mice model for the study of RR-multiple sclerosis). RESULTS: We demonstrate that SJL-AdMSCs show the same fibroblastic shape, growth rate, profile of markers expression and multipotency described for MSCs in every passage evaluated (up to passage 15). Additionally, SJL-AdMSCs ameliorate the RR-EAE course, suggesting that they could modulate disease progression. Moreover, their features studied are fully comparable with the standardized Ad-MSCs obtained from the C57BL/6 mouse strain, which strengthens their use in cell therapy. CONCLUSION: SJL-AdMSCs might be a suitable source of Ad-MSCs for studies related to the properties of MSCs and their application as promising therapeutic tools in autologous transplants in experimental medicine. PMID: 25498031 [PubMed - as supplied by publisher]
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ROR nuclear receptors: structures, related diseases, and drug discovery. Acta Pharmacol Sin. 2014 Dec 15; Authors: Zhang Y, Luo XY, Wu DH, Xu Y Abstract Nuclear receptors (NRs) are ligand-regulated transcription factors that regulate metabolism, development and immunity. The NR superfamily is one of the major classes of drug targets for human diseases. Retinoic acid receptor-related orphan receptor (ROR) α, β and γ belong to the NR superfamily, and these receptors are still considered as 'orphan' receptors because the identification of their endogenous ligands has been controversial. Recent studies have demonstrated that these receptors are regulated by synthetic ligands, thus emerge as important drug targets for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, etc. Studying the structural basis and ligand development of RORs will pave the way for a better understanding of the roles of these receptors in human diseases. Here, we review the structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs. PMID: 25500868 [PubMed - as supplied by publisher]
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