Multiple Sclerosis and Stem Cell Therapy


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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

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 – in process]

Gene therapy of multiple sclerosis using interferon β-secreting human bone marrow mesenchymal stem cells.

Biomed Res Int. 2013;2013:696738
Authors: Ryu CH, Park KY, Hou Y, Jeong CH, Kim SM, Jeun SS

Interferon-beta (IFN- β ), a well-established standard treatment for multiple sclerosis (MS), has proved to exhibit clinical efficacy. In this study, we first evaluated the therapeutic effects for MS using human bone marrow-derived mesenchymal stem cells (hBM-MSCs) as delivery vehicles with lesion-targeting capability and IFN- β as therapeutic gene. We also engineered hBM-MSCs to secret IFN- β (MSCs-IFN β ) via adenoviral transduction and confirmed the secretory capacity of MSCs-IFN β by an ELISA assay. MSCs-IFN β -treated mice showed inhibition of experimental autoimmune encephalomyelitis (EAE) onset, and the maximum and average score for all animals in each group was significantly lower in the MSCs-IFN β -treated EAE mice when compared with the MSCs-GFP-treated EAE mice. Inflammatory infiltration and demyelination in the lumbar spinal cord also significantly decreased in the MSCs-IFN β -treated EAE mice compared to PBS- or MSCs-GFP-treated EAE mice. Moreover, MSCs-IFN β treatment enhanced the immunomodulatory effects, which suppressed proinflammatory cytokines (IFN-γ and TNF-α) and conversely increased anti-inflammatory cytokines (IL-4 and IL-10). Importantly, injected MSCs-IFN β migrated into inflamed CNS and significantly reduced further injury of blood-brain barrier (BBB) permeability in EAE mice. Thus, our results provide the rationale for designing novel experimental protocols to enhance the therapeutic effects for MS using hBM-MSCs as an effective gene vehicle to deliver the therapeutic cytokines.

PMID: 23710456 [PubMed – indexed for MEDLINE]

Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells

Arch Med Res. 2013 May;44(4):266-72
Authors: Mohyeddin Bonab M, Mohajeri M, Sahraian MA, Yazdanifar M, Aghsaie A, Farazmand A, Nikbin B

BACKGROUND AND AIMS: Mesenchymal stem cells (MSC) are currently strong candidates for stem cell therapy. Cytokines have a profound effect on the resultant immune responses. This study aims to evaluate variations in the cytokine profile of multiple sclerosis patients treated with autologous MSC.

METHODS: Twenty five patients received one dose of intrathecal MSCs (mean number: 29.5 × 10⁶). To measure the gene expression of FOXP3, IFN-γ, TGF-β, IL-4, IL-10, IL-6, and their serum proteins, samples were collected at five intervals: day 0 prior to injection and months 1, 3, 6, and 12 after MSC therapy. Gene expression was evaluated via real-time PCR and protein values were measured by ELISA.

RESULTS: There were no statistically significant variations in gene expression and serum level of cytokines after a 1-year follow-up of MSC-treated MS patients. The only correlation found was an increase in IL-6 gene expression in patients with progressive disease.

CONCLUSION: Intrathecal injection of MSCs does not affect cytokine variation in peripheral blood. Because the condition of most of our patients either improved or stabilized after stem cell therapy (SCT), we speculate that the immunomodulatory or neuroregenerative effects of MSC are exerted locally in the central nervous system.

PMID: 23684533 [PubMed – indexed for MEDLINE]

17β-Estradiol enhances the efficacy of adipose-derived mesenchymal stem cells on remyelination in mouse model of multiple sclerosis

Acta Med Iran. 2012;50(12):789-97
Authors: Ragerdi Kashani I, Hedayatpour A, Pasbakhsh P, Kafami L, Atlasi N, Pirhajati Mahabadi V, Mamoudi R, Baazm M

Previous studies have demonstrated the potential of monotherapy with either mesenchymal stem cells (MSCs) or estrogen in autoimmune and cuprizone models of multiple sclerosis (MS). The aim of this study was to examine the effects of co-administration of 17β-estradiol (E2) and adipose-derived mesenchymal stem cells (ADSCs) on remyelination of corpus callosum axons in a cuprizone model of MS. Forty eight male C57BL/6 mice were fed cuprizone (0.2%) for 6 weeks. At day 0 after cuprizone removal, animals were randomly divided into four groups. The E2 monotherapy, ADSCs monotherapy, E2/ADSCs combined therapy and vehicle control. Some mice of the same age were fed with their normal diet to serve as healthy control group. E2 pellets, designed to release 5.0 mg E2 over 10 days, were implanted subcutaneously. 10(6) PKH26 labeled ADSCs were transplanted into lateral tail. The extent of demyelination, remyelination, and cell type’s composition of host brain were examined at 10 days post-transplantation in the body of the corpus callosum. Transplanted cells migrated to the corpus callosum injury. Histological examination revealed efficacy of intravenous ADSCs transplantation in remyelination of mouse cuprizone model of MS can be significantly enhanced by E2 administration. Flow cytometry showed that the mean percentages of expression of Iba-1, Olig2 and O4 were significantly increased in E2/ADSCs combined therapy in comparison with ADSCs monotherapy. In conclusion, the findings of this study revealed that E2 administration enhanced efficacy of intravenous ADSCs transplantation in remyelination of corpus callosum axons in mouse cuprizone model of MS.

PMID: 23456519 [PubMed – indexed for MEDLINE]

Characterization of autologous mesenchymal stem cell-derived neural progenitors as a feasible source of stem cells for central nervous system applications in multiple sclerosis

Stem Cells Transl Med. 2012 Jul;1(7):536-47
Authors: Harris VK, Faroqui R, Vyshkina T, Sadiq SA

Bone marrow mesenchymal stem cell-derived neural progenitors (MSC-NPs) are a potential therapeutic source of cells that have been shown to be efficacious in a preclinical model of multiple sclerosis (MS). To examine the feasibility of using MSC-NPs as an autologous source of cells to promote central nervous system (CNS) repair in MS, this study characterized human MSC-NPs from a panel of both MS and non-MS donors. Expanded MSCs showed similar characteristics in terms of growth and cell surface phenotype, regardless of the donor disease status. MSC-NPs derived from all MSCs showed a consistent pattern of gene expression changes that correlated with neural commitment and increased homogeneity. Furthermore, the reduced expression of mesodermal markers and reduced capacity for adipogenic or osteogenic differentiation in MSC-NPs compared with MSCs suggested that MSC-NPs have reduced potential of unwanted mesodermal differentiation upon CNS transplantation. The immunoregulatory function of MSC-NPs was similar to that of MSCs in their ability to suppress T-cell proliferation and to promote expansion of FoxP3-positive T regulatory cells in vitro. In addition, MSC-NPs promoted oligodendroglial differentiation from brain-derived neural stem cells that correlated with the secretion of bioactive factors. Our results provide a set of identity characteristics for autologous MSC-NPs and suggest that the in vitro immunoregulatory and trophic properties of these cells may have therapeutic value in the treatment of MS.

PMID: 23197858 [PubMed – indexed for MEDLINE]

In vitro assessment of mesenchymal stem cells immunosuppressive potential in multiple sclerosis patients

Immunol Lett. 2013 Jan;149(1-2):9-18
Authors: Zafranskaya MM, Nizheharodova DB, Yurkevich MY, Lamouskaya NV, Motuzova YM, Bagatka SS, Ivanchik HI, Fedulov AS

Mesenchymal stem cells (MSC) are promising for multiple sclerosis (MS) treatment. However, clinical results remain controversial, and no criteria are available for predicting the efficiency of MSC therapy. Using an in vitro model of lymphocytes and MSC cocultivation we revealed that the Index of MSC Suppression of myelin-induced memory T cells proliferation was stronger than that of PHA-stimulated proliferation and inversely correlated with patients’EDSS score. In vitro expression of CD119 (IFNGR1) in mitogen/myelin-stimulated T cells increased in the presence of MSC being inversely correlated with T-lymphocytes proliferation. The Index of MSC Suppression and CD119 expression in T-lymphocytes may be useful when assessing MSC immunosuppressive potential in MS patients.

PMID: 23089549 [PubMed – indexed for MEDLINE]

Mesenchymal stem cells expressing vasoactive intestinal peptide ameliorate symptoms in a model of chronic multiple sclerosis

Cell Transplant. 2013;22(5):839-54
Authors: Cobo M, Anderson P, Benabdellah K, Toscano MG, Muñoz P, García-Pérez A, Gutierrez I, Delgado M, Martin F

Multiple sclerosis (MS) is a severe debilitating disorder characterized by progressive demyelination and axonal damage of the central nervous system (CNS). Current therapies for MS inhibit the immune response and demonstrate reasonable benefits if applied during the early phase of relapsing–remitting MS (RRMS) while there are no treatments for patients that progress neither to the chronic phase nor for the primary progressive form of the disease. In this manuscript, we have studied the therapeutic efficacy of a cell and gene therapy strategy for the treatment of a mouse model of chronic MS [myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE)]. We used allogenic mesenchymal stem cells (MSCs) asa therapeutic tool and also as vehicle to deliver fully processed 3.3-kDa vasoactive intestinal peptide (VIP) to the peripheral immune organs and to the inflamed CNS. Intraperitoneal administrations of MSCs expressing VIP stopped progression and reduced symptoms when administered at peak of disease. The improvement in clinical score correlated with diminished peripheral T-cell responses against MOG as well as lower inflammation,lower demyelination, and higher neuronal integrity in the CNS. Interestingly, neither lentiviral vectors expressing VIP nor unmodified MSCs were therapeutic when administer at the peak of disease. The increased therapeutic effect of MSCs expressing VIP over unmodified MSCs requires the immunoregulatory and neuroprotective roles of both VIP and MSCs and the ability of the MSCs to migrate to peripheral lymph organs and the inflamed CNS.

PMID: 23031550 [PubMed – indexed for MEDLINE]

The Immunomodulatory and Neuroprotective Effects of Mesenchymal Stem Cells (MSCs) in Experimental Autoimmune Encephalomyelitis (EAE): A Model of Multiple Sclerosis (MS)

Int J Mol Sci. 2012;13(7):9298-331
Authors: Al Jumah MA, Abumaree MH

Mesenchymal stem cells (MSCs) are multipotent cells that differentiate into the mesenchymal lineages of adipocytes, osteocytes and chondrocytes. MSCs can also transdifferentiate and thereby cross lineage barriers, differentiating for example into neurons under certain experimental conditions. MSCs have anti-proliferative, anti-inflammatory and anti-apoptotic effects on neurons. Therefore, MSCs were tested in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), for their effectiveness in modulating the pathogenic process in EAE to develop effective therapies for MS. The data in the literature have shown that MSCs can inhibit the functions of autoreactive T cells in EAE and that this immunomodulation can be neuroprotective. In addition, MSCs can rescue neural cells via a mechanism that is mediated by soluble factors, which provide a suitable environment for neuron regeneration, remyelination and cerebral blood flow improvement. In this review, we discuss the effectiveness of MSCs in modulating the immunopathogenic process and in providing neuroprotection in EAE.

PMID: 22942767 [PubMed]

Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study

Lancet Neurol. 2012 Feb;11(2):150-6

Authors: Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, Du MQ, Luan SL, Altmann DR, Thompson AJ, Compston A, Scott MA, Miller DH, Chandran S

BACKGROUND: More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis.

METHODS: Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with, number NCT00395200.

FINDINGS: We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio.

INTERPRETATION: Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection.

FUNDING: Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.

PMID: 22236384 [PubMed – indexed for MEDLINE]

Transplantation of mesenchymal stem cells in multiple sclerosis

Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111(2 Pt 2):72-6
Authors: Odinak MM, Bisaga GN, Novitskiĭ AV, Tyrenko VV, Fominykh MS, Bilibina AA, Krugliakov PV, Polyntsev DG

To assess safety and tolerability of treatment with autologic multipotent mesenchymal stem cells (MSC) in multiple sclerosis (MS), we have obtained autologic red bone marrow-derived MSC from 8 patients. Proliferation, immunophenotype and caryotype of MSC, their sterility, the absence of hemopoetic cells, chromosomal aberrations and signs of aging were controlled during the cell growth. The inverse injection of MSC in patient’s blood was conducted in accordance to the elaborated protocol in a short intravenous infusion in dose 2.0 x 10(6)/kg of body mass once in 30 days. The duration of treatment was from 4 to 8 months. The efficacy of treatment was assessed after 4, 8 and 12 months. All patients tolerated repeated intravenous infusions of autologic MSC well with no significant side-effects as in the early as well in the remote periods of treatment. The distinct positive effect was seen in some cases 2 months after the beginning of treatment. The improvement of 0.5 point on EDSS was seen in 5/8 patients after 4 months. After 12 months, the improvement of 0.5-1 point on EDSS was seen in 6/8, stabilization in 1/8, progression in 1/8. These results revealed the safety of the elaborated protocol of treatment and the moderate clinical efficacy of treatment in non-curable patients or those with poor response to treatment that suggested continuing the study and enrollment of new patients.

PMID: 21919233 [PubMed – indexed for MEDLINE]

Harnessing the therapeutic potential of mesenchymal stem cells in multiple sclerosis

Expert Rev Neurother. 2011 Sep;11(9):1295-303
Authors: Darlington PJ, Boivin MN, Bar-Or A

Phase I clinical trials exploring the use of autologous mesenchymal stem cell (MSC) therapy for the treatment of multiple sclerosis (MS) have begun in a number of centers across the world. MS is a complex and chronic immune-mediated and neurodegenerative disease influenced by genetic susceptibility and environmental risk factors. The ideal treatment for MS would involve both attenuation of detrimental inflammatory responses, and induction of a degree of tissue protection/regeneration within the CNS. Preclinical studies have demonstrated that both human-derived and murine-derived MSCs are able to improve outcomes in the animal model of MS, experimental autoimmune encephalomyelitis. How MSCs ameliorate experimental autoimmune encephalomyelitis is being intensely investigated. One of the major mechanisms of action of MSC therapy is to inhibit various components of the immune system that contribute to tissue destruction. Emerging evidence now supports the idea that MSCs can access the CNS where they can provide protection against tissue damage, and may facilitate tissue regeneration through the production of growth factors. The prospect of cell-based therapy using MSCs has several advantages, including the relative ease with which they can be extracted from autologous bone marrow or adipose tissue and expanded in vitro to reach the purity and numbers required for transplantation, and the fact that MSC therapy has already been used in other human disease settings, such as graft-versus-host and cardiac disease, with initial reports indicating a good safety profile. This article will focus on the theoretical and practical issues relevant to considerations of MSC therapy in the context of MS.

PMID: 21864075 [PubMed – indexed for MEDLINE]

How safe could intrathecal transplantation of mesenchymal stem cells be considered in multiple sclerosis?

Arch Neurol. 2011 Jul;68(7):955; authors reply 955-6
Authors: Karacostas D, Hadjigeorgiou G, Ioannidis P, Milonas I

PMID: 21747040 [PubMed – indexed for MEDLINE]

Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases

Lancet Neurol. 2011 Jul;10(7):649-56
Authors: Uccelli A, Laroni A, Freedman MS

The rationale for use of adult stem cells as a treatment for neurological diseases such as multiple sclerosis arose from the hope that they had the capacity to foster repair of the CNS through tissue integration and differentiation into neural cells. Evidence from preclinical studies suggested that mesenchymal stem cells (MSCs), a subset of adult progenitor cells, are an effective therapy in preclinical animal models of neurological diseases such as experimental autoimmune encephalomyelitis, a model for multiple sclerosis, and stroke. In experimental autoimmune encephalomyelitis, intravenous injection of MSCs ameliorates clinical course and decreases demyelination, immune infiltrates, and axonal loss. Surprisingly, these effects do not require full CNS engraftment by MSCs, but rely on the capacity of MSCs to inhibit pathogenic immune responses and release neuroprotective and pro-oligodendrogenic molecules favouring tissue repair. These results led to the conclusion that therapeutic use of MSCs should initially focus on individuals with multiple sclerosis and persistent inflammation. Small clinical studies in different neurological diseases have suggested that MSCs are safe, paving the road for larger phase 2 studies addressing the effect of MSCs on clinical outcomes and markers of disease activity.

PMID: 21683930 [PubMed – indexed for MEDLINE]

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

Trials. 2011;12:62
Authors: Connick P, Kolappan M, Patani R, Scott MA, Crawley C, He XL, Richardson K, Barber K, Webber DJ, Wheeler-Kingshott CA, Tozer DJ, Samson RS, Thomas DL, Du MQ, Luan SL, Michell AW, Altmann DR, Thompson AJ, Miller DH, Compston A, Chandran S

BACKGROUND: No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes–the “sentinel lesion approach”.

METHODS/DESIGN: MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway.

RESULTS: Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm.

CONCLUSIONS: In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS–the sentinel lesion approach–serving as proof of principle for its future wider applicability.

PMID: 21366911 [PubMed – indexed for MEDLINE]

Mesenchymal stem cells for multiple sclerosis: does neural differentiation really matter?

Curr Stem Cell Res Ther. 2011 Mar;6(1):69-72
Authors: Uccelli A, Morando S, Bonanno S, Bonanni I, Leonardi A, Mancardi G

The lack of therapies fostering remyelination and regeneration of the neural network deranged by the autoimmune attack occurring in multiple sclerosis (MS), is raising great expectations about stem cells therapies for tissue repair. Mesenchymal stem cells (MSCs) have been proposed as a possible treatment for MS due to the reported capacity of transdifferentiation into neural cells and their ability at modulating immune responses. However, recent studies have demonstrated that many other functional properties are likely to play a role in the therapeutic plasticity of MSCs, including anti-apoptotic, trophic and anti-oxidant effects. These features are mostly based on the paracrine release of soluble molecules, often dictated by local environmental cues. Based on the modest evidence of long-term engraftment and the striking clinical effects that are observed immediately after MSCs administration in the experimental model of MS, we do not favor a major role for transdifferentiation as an important mechanism involved in the therapeutic effect of MSCs.

PMID: 20955153 [PubMed – indexed for MEDLINE]

Reciprocal Th1 and Th17 regulation by mesenchymal stem cells: Implication for multiple sclerosis

Ann Neurol. 2010 Oct;68(4):540-5
Authors: Darlington PJ, Boivin MN, Renoux C, François M, Galipeau J, Freedman MS, Atkins HL, Cohen JA, Solchaga L, Bar-Or A

Human mesenchymal stem cells (hMSCs) are being considered for clinical trials of multiple sclerosis (MS). We examined the effects of adult bone marrow-derived hMSCs on responses of primary human Th1, Th17, and Th1/17 double-expressing T-cell subsets, all implicated in MS. As expected, soluble products from hMSCs inhibited Th1 responses; however, Th17 responses were increased. Secretion of interleukin (IL)-10, considered anti-inflammatory, was decreased. Pretreating hMSCs with the proinflammatory cytokine IL-1β accentuated these effects, and caused decreases in the Th1/17 subset. These findings underscore the importance of further preclinical work and immune-monitoring to define hMSC effects on disease-relevant immune responses under variable conditions.

PMID: 20661924 [PubMed – indexed for MEDLINE]

Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis

Mult Scler. 2010 Aug;16(8):909-18

Authors: Mallam E, Kemp K, Wilkins A, Rice C, Scolding N

Recent studies have investigated the potential of autologous bone marrow-derived mesenchymal stem cells (MSCs) as a therapy for multiple sclerosis. Whether MSCs from individuals with multiple sclerosis are functionally and/or phenotypically abnormal has received less attention. Through our Phase I clinical trial, SIAMMS, we were able to isolate and characterize MSCs from individuals with multiple sclerosis. The objective of the study was to demonstrate that MSCs from individuals with multiple sclerosis show no significant differences from MSCs derived from individuals without multiple sclerosis. MSCs were isolated from bone marrow aspirates from four SIAMMS participants. We were also able to isolate MSCs from bone marrow obtained during a total hip replacement operation on an individual with multiple sclerosis. Control MSCs were isolated from bone marrow acquired during total hip replacement operations on five individuals without MS. MSCs were characterized using standard criteria: plastic adherence, differentiation along adipogenic/osteogenic/chondrogenic lineages, and expression of specific cell surface antigens. We also determined their proliferation potential. MSCs from individuals with multiple sclerosis and individuals without multiple sclerosis were similar in proliferation, differentiation potential and cell surface antigen expression. This has relevance to scientific studies investigating the therapeutic potential of autologous MSCs which primarily utilize MSCs from individuals without multiple sclerosis, and relevance to clinical studies extrapolating from these scientific findings.

PMID: 20542920 [PubMed – indexed for MEDLINE]

Mesenchymal stem cells for multiple sclerosis: can we find the answer?

Mult Scler. 2010 Apr;16(4):386
Authors: Tyndall A, EULAR Stromal Cell Translational Group

PMID: 20385716 [PubMed – indexed for MEDLINE]

Intracerebroventricular transplantation of human mesenchymal stem cells induced to secrete neurotrophic factors attenuates clinical symptoms in a mouse model of multiple sclerosis

J Mol Neurosci. 2010 May;41(1):129-37
Authors: Barhum Y, Gai-Castro S, Bahat-Stromza M, Barzilay R, Melamed E, Offen D

Stem cell-based therapy holds great potential for future treatment of multiple sclerosis (MS). Bone marrow mesenchymal stem cells (MSCs) were previously reported to ameliorate symptoms in mouse MS models (experimental autoimmune encephalomyelitis, EAE). In this study, we induced MSCs to differentiate in vitro into neurotrophic factor-producing cells (NTFCs). Our main goal was to examine the clinical use of NTFCs on EAE symptoms. The NTFCs and MSCs were transplanted intracerebroventricularly (ICV) to EAE mice. We found that NTFCs transplantations resulted in a delay of symptom onset and increased animal survival. Transplantation of MSCs also exerted a positive effect but to a lesser extent. In vitro analysis demonstrated the NTFCs’ capacity to suppress mice immune cells and protect neuronal cells from oxidative insult. Our results indicate that NTFCs-transplanted ICV delay disease symptoms of EAE mice, possibly via neuroprotection and immunomodulation, and may serve as a possible treatment to MS.

PMID: 19902385 [PubMed – indexed for MEDLINE]

Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis.
Mult Scler. 2009 May;15(5):644-6

Authors: Liang J, Zhang H, Hua B, Wang H, Wang J, Han Z, Sun L

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system. Umbilical cord derived mesenchymal stem cells are immunosuppressive. We transplanted mesenchymal stem cells in a patient with refractory progressive MS, and the disease course was stabilized after the transplantation. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.

PMID: 19389752 [PubMed – indexed for MEDLINE]

Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis

Glia. 2009 Aug 15;57(11):1192-203
Authors: Bai L, Lennon DP, Eaton V, Maier K, Caplan AI, Miller SD, Miller RH

Cell-based therapies are attractive approaches to promote myelin repair. Recent studies demonstrated a reduction in disease burden in mice with experimental allergic encephalomyelitis (EAE) treated with mouse mesenchymal stem cells (MSCs). Here, we demonstrated human bone marrow-derived MSCs (BM-hMSCs) promote functional recovery in both chronic and relapsing-remitting models of mouse EAE, traced their migration into the injured CNS and assayed their ability to modulate disease progression and the host immune response. Injected BM-hMSCs accumulated in the CNS, reduced the extent of damage and increased oligodendrocyte lineage cells in lesion areas. The increase in oligodendrocytes in lesions may reflect BM-hMSC-induced changes in neural fate determination, since neurospheres from treated animals gave rise to more oligodendrocytes and less astrocytes than nontreated neurospheres. Host immune responses were also influenced by BM-hMSCs. Inflammatory T-cells including interferon gamma producing Th1 cells and IL-17 producing Th17 inflammatory cells and their associated cytokines were reduced along with concomitant increases in IL-4 producing Th2 cells and anti-inflammatory cytokines. Together, these data suggest that the BM-hMSCs represent a viable option for therapeutic approaches.

PMID: 19191336 [PubMed – indexed for MEDLINE]

Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): a proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases

J Neurol Sci. 2008 Feb 15;265(1-2):131-5
Authors: Karussis D, Kassis I, Kurkalli BG, Slavin S

Bone marrow (BM) derived mesenchymal stem cells (MSCs) (non-hematopoietic, stromal cells) can differentiate under certain circumstances into cells from various neuronal and glial type lineages; they also exert immunomodulatory effects. For potential clinical applications, BM-MSCs offer significant practical advantages over other types of stem cells, since they can be obtained from the adult BM (the patient himself being the donor) and can be easily cultured and expanded posing in parallel a very low risk for development of malignancies. We have shown that BM-MSCs cultured with a cocktail of growth factors (containing FGF and BDNF) differentiate into neuronal/glial lineage cells with a predominance of cells expressing astrocytes’ markers. BM-MSCs were effective in suppression of chronic EAE in mice and induced neuroprotection, preserving most of the axons in the CNS of successfully-treated animals. Histopathological studies revealed that MSCs could efficiently migrate into the CNS inflamed tissue (both when administered intravenously and intraventricularly) and differentiated into cells expressing neural-glial lineage markers. Our preclinical results indicate that bone marrow can provide a source of stem cells with a potential for migration into inflamed CNS tissue and differentiation into cells expressing neuronal and glial cell markers. Such an approach may provide a feasible and practical way for in situ immunomodulation, neuroprotection and possibly remyelination/regeneration in diseases like multiple sclerosis. We therefore developed a explorative protocol for the evaluation of this therapeutic approach in a small group of patients with MS and other neurodegenerative diseases.

PMID: 17610906 [PubMed – indexed for MEDLINE]