https://doi.org/10.5812/archneurosci.21564

Stem Cell Therapy ‒ Approach for Multiple Sclerosis Treatment

authors:

avatar Masoud Soleimani 1 , 2 , avatar Hamid Reza Aghayan 1 , 3 , avatar Parisa Goodarzi 1 , avatar Majid Farshdousti Hagh 4 , avatar Abdolreza Ardeshiry Lajimi 5 , avatar Najmaldin Saki 6 , avatar Fereshteh Mohamadi Jahani 1 , avatar Abbas Norouzi Javidan 1 , avatar Babak Arjmand 7 , *

Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, IR Iran
Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, IR Iran
Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, IR Iran
Division of Laboratory Hematology and Blood Banking, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, IR Iran
Young Researchers Club, Science and Research Branch, Islamic Azad University, Tehran, IR Iran
Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, IR Iran
Archives of Neuroscience: Vol.3, issue 1; e21564
published online: January 30, 2016
article type: Review Article
received: June 29, 2014
revised: December 1, 2014
accepted: May 6, 2015

how to cite: Soleimani M, Aghayan H R, Goodarzi P, Farshdousti Hagh M, Ardeshiry Lajimi A, et al. Stem Cell Therapy ‒ Approach for Multiple Sclerosis Treatment. Arch Neurosci. 2016;3(1):e21564. https://doi.org/10.5812/archneurosci.21564.

Abstract

Context:

Multiple sclerosis (MS) is an autoimmune and inflammatory disease that affects the central nervous system (CNS). In MS, activated T-cells for self-antigens, such as myelin, attack erroneous targets in the CNS and result in axonal demyelination and neurological disability. Stem cell (SC) therapy has potential applications in treating neurological disorders.

Evidence Acquisition:

The reasoning for use of SCs from different sources, as a therapeutic option in MS, arose from the expectation that they have the capacity to remyelinate and differentiate into oligodendrocyte precursor cells. Many SC types are under testing for treating MS and, the most common, are neural SC (NSC), embryonic SC (ESC), mesenchymal SC (MSC) and hematopoietic SC (HSC).

Results:

The NSCs, namely adult NSCs, bone marrow-derived-NSCs and neural progenitor cells, are capable of differentiation into oligodendrocytes and induce remyelination. The MSCs influence on the rate of repair of all endogenous progenitors. The autologous HSC transplantation is an option in cases that do not respond to standard therapy and also meliorate the symptoms and limit progression of disease. The ESCs have shown neuroprotection in cases of MS, through a yet unclear immunosuppression mechanism.

Conclusions:

Recently, cell transplantation has introduced a novel approach for treatment of neurological disorders, such as MS. Therefore, focusing on safety issues, while bridging from the basic SC sciences to the clinical transplantation trials, has a crucial role in cellular therapy programs. This review will discuss in detail the experimental and clinical use of these SC populations and their probably mechanisms in the treatment of multiple sclerosis.

1. Context

Multiple sclerosis (MS) is an autoimmune and chronic inflammatory multifocal demyelinating disease of the central nervous system (CNS) (1-12). Demyelination can occur via hereditary demyelinating and metabolic disorders, viral infections, nutritional and toxic disorders, and also in association with trauma and stroke, known as CNS lesions. The MS is characterized by three mechanisms, including demyelination, remyelination failure and axonal loss. In order to select the best approach for MS treatment, two objectives must be kept in mind: to prevent progression and to repair damages that have already been constituted (13-15). There are different medications that were introduced for the treatment of patients with relapsing MS, such as interferon beta-1a (Avonex®, Biogen, Cambridge, MA, USA/Rebif®, Merk Serono, Darmstadt, Germany), recombinant interferon β-1b (Betaferon®, Boehringer Ingelheim, Ingelheim, Germany), natalizumab, as a α4 integrin antagonist monoclonal antibody (Tysabri®, Biogen, Cambridge, MA, USA), teriflunomide (Aubagio®, Genzyme, Cambridge, MA, USA), dimethyl fumarate (Tecfidera®, Biogen, Cambridge, MA, USA), alemtuzumab (Lemtrada®, Genzyme, Cambridge, MA, USA), clatiramer acetate (Copaxone®, Teva Pharmaceutical Industries, Petah Tikva, Israel), fingolimod (Gilenya®, Novartis, Basel, Switzerland), etc. (3, 9, 16-25). Although several patients with MS respond fairly well to these medications, others continue to show deterioration in motor and cognitive functions (20). Nowadays, another approach for the treatment of MS is stem cells (SCs) therapy. The SCs are unspecialized cells that belong to the group of multipotent cells. Although these cells are undifferentiated, they are capable to proliferate or reproduce themselves, and they can differentiate into other types of body cells, with specialized functions (26). The SCs have been regarded as a promising treatment for neurodegenerative disease, such as MS (27, 28). There are many investigations about the potential of four SC types, including neural stem cells (NSCs), embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), and non-expanded adipose stromal vascular fraction or expanded adipose tissue-derived MSCs in MS stem cell therapy (1, 29, 30). Therefore, we will review their capability in the treatment of MS.

2. Evidence Acquisition

2.1. Search Strategy

This review was performed using “cell therapy”, “mesenchymal stem cells”, “Multiple sclerosis”, “stem cells”, and “stem cell transplantation”, as search terms, and PubMed, as search engine. Subsequently, the search period was set from 1988 to 2014.

2.2. A Brief History of Stem Cell Therapy for Multiple Sclerosis

In 1977, exogenous myelinating cells were injected into demyelinated lesions, in the CNS, by Bill Blakemore. He demonstrated successful remyelination in CNS after cell transplantation. Similar studies showed promising results and cell therapy was suggested for treatment of neurodegenerative disorders, such as MS. After about four decades, findings of several clinical cell transplantation trials on MS were reported. In most of these studies, autologous bone marrow derived SCs were injected, intravenously (31). Furthermore, in 1995, autologous HSC transplantation was performed for refractory MS (11). Recently, SC therapy has been recommended for treatment of various degenerative diseases, including MS (1, 6), using different types of SCs (4, 32, 33).

2.3. Potential of Neural Stem Cells for the Treatment of Multiple Sclerosis

The NSCs can be isolated from the adult CNS, from the subventricular zone (SVZ) of the lateral ventricle wall, which is a major germinal region that is used for isolation of NSCs and, consequently, are termed as SVZ-NSCs (34, 35). The fundamental properties of these cells are self-renewal, multipotency and long distance migration, within the inflamed CNS (36-41). These properties make NSCs suitable for cellular therapy in brain. However, there is increasing evidence that NSCs have neuroprotective and immunomodulatory properties (42-46). Many studies exist that reported beneficial effects of NSCs therapy, in neurologic disorders, in several animal models of different neurologic disease, such as: Huntington disease, Parkinson disease (PD), MS, stroke, spinal cord injuries and amyotrophic lateral sclerosis (47). Therefore, for NSCs to be useful in the treatment of MS, they would need to differentiate into both oligodendrocytes and neurons. Several investigations have shown that NSCs can differentiate into mature oligodendrocytes, in animal models of dysmiyelination (43, 48-53) and neurons, in animal model of cerebral degeneration (54). Recently, other investigations reported the therapeutic potential of adult NSCs (aNSCs) in MS (40, 42, 43, 55). Another type of NSCs, investigated in neurodegenerative diseases, are bone marrow-derived NSCs (BM-NSCs), and these cells have neurogeneratory potential and immunomodulatory effects (56, 57). The BM-NSCs are preferred to SVZ-NSCs, through ethics. Neural progenitor cells (NPCs) are other neural cells that, similarly to NSCs, are capable of differentiation into oligodendrocytes and remyelination. Furthermore, NPCs have anti-inflammatory properties in the CNS, by producing a variety of cytokines and neutrophins (58, 59). These findings clearly confirmed the tremendous potential of NSCs therapy for the treatment of patients with MS, even though it seems that more investigations are need for the confirmation of viability of the method of hNSCs isolation and evaluation of clinical efficacy of NSCs therapy, in animal model.

2.4. Mesenchymal Stem Cells as a Therapeutic Strategy for Multiple Sclerosis

The MSCs are capable transdifferentiation into cells of the endodermal and ectodermal origin, including possible neural transdifferentiation and immunomodulating properties. Because of this ability of MSCs, they have been described as multipotent stromal cells (60-63). These cells can be prepared from a variety of sources, including bone marrow, amniotic fluid, deciduous teeth, adipose tissue, umbilical cord, synovial membranes, peripheral blood, etc. However, bone marrow has been shown as the main source of MSCs (64-69). Recently, numerous studies have focused on MSCs, for cell therapy in many neurodegenerative disorders, including MS (70-73). There are several clinical trials and, also, basic studies that used human MSCs, as a candidate for treatment of MS (Table 1). The MSCs can migrate into injured CNS and differentiate into cells expressing neural and glial cell markers (74). Indeed, MSCs can differentiate into neuronal cells and this differentiation is confirmed by biomedical, anatomical and electrophysiological characteristics (75). Harris et al. investigated the potential of MSCs on promoting repair and recovery after intrathecal injection, into mice with experimental autoimmune encephalomyelitis (EAE). Their results had shown an improved neurological function, compared to controls, and suggested that MSCs can influence the rate of repair of all endogenous progenitors in spinal cords. Therefore, MSCs can be used in MS patients for promoting CNS repair (76). Reduction of expanded disability status scale (EDSS) was observed when Karussis et al. used autologous MSCs injected intrathecal plus intravenous, in patients with MS (77). Investigations of the effects of intrathecal injection of autologous MSCs in MS patients have shown clinical improvement in treated patients (78). Neurotrophin-3 (NT-3)-modified MSCs, via recombinant adenoviral vector (Adv), implanted into a region of ethidium bromide (EB) induced remyelination in the rats with demyelinated spinal cord. Results have shown that AdvNT-3-MSC implants upgrade the endogenous remyelinating cells, to participate directly in myelination. These data suggest that genetically modification of MSCs could be a potential therapeutic approach for elevating the efficacy of MSC treatment for MS and other neurodegenerative disease (79). However, our data and other publications, about the use of MSCs in MS patients, have revealed the feasibility and safety of MSC therapy.

Table 1.

Published Studies Using Human Mesenchymal or Mononuclear Stem Cells for the Treatment of Multiple Sclerosisa

Stem Cell TypeNumber of PatientsType of DiseaseRoute of AdministrationStudy FindingsPhaseRef.
Bone marrow MSCs15advanced MSintrathecal, intravenousclinical feasibility, safety, and immediate immunomodulatory effects - no major adverse effectsI, II(77)
Bone marrow MSCs10advanced MS, relapsing-remitting MS, and secondary progressive MSintrathecalclinical not radiological efficacy - no adverse effectI(78)
Bone marrow MSCs25advanced MSintrathecalimprovement and stabilization of the disease course - no adverse effectI(80)
Unsorted bone marrow stem cells6relapsing progressive MSintravenoustherapeutic potentialI(81)
Bone marrow MSCs10secondary progressive MSintravenousevidences of structural, functional, and physiological improvementI/IIa(82, 83)
Bone marrow MSCs derived neural stem cells---influence the rate of repair through effects on endogenous progenitors in the spinal cord in MSin vitro study(84)
Bone marrow MSCs8progressive MSintravenoussafety of the protocol and the moderate clinical efficacy - After 12 months, the improvement and stabilization - no significant side-effectsI(85)
Bone marrow MSCs7relapsing-remitting MSintrathecalMSCs effectiveness in obtaining a sufficient number of Treg lymphocytes-(86)
Bone marrow MSCs---monitoring the immunological effects of MSCsin vitro study(87)
Allogeneic umbilical cord MSCs 1primary progressive MSintrathecal, intravenousa potent immunosuppressive effect-(88)
Bone marrow MSCs10primary and secondary progressive MSintrathecalfunctional improvement in pyramidal, cerebellar and sensory pathways, and bowel function in some patients - decreasing in the number of plaques in one patient in MRII(89)
Human placenta MSCs16secondary progressive and relapsing MSintravenoussafety and well tolerability - mild to moderate adverse events (headache, nausea, infusion site reactions)Ib(90)
Bone marrow MSCs25relapsing-remitting, secondary progressive, progressive relapsing-MSCs inhibit proliferation of mitogen/myelin-stimulated T Cells in MS patient - immune suppression by MSC in MS patientsin vitro study(7)

aAbbreviations: MS: Multiple sclerosis; MSCs: Mesenchymal stem cells.

2.5. Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Hematopoietic stem cells (HSCs) are multipotent SCs that give rise to all the blood cell types, from the lymphoid and myeloid lineages. There has been an increasing use of HSC transplantation (HSCT) over the last years, for the treatment of hematological and non-hematological neoplasms and several autoimmune diseases, including MS (91, 92). More than 600 published reports investigated bone marrow HSCT for the treatment of MS (93-95). The identifying characteristic of MS is inflammatory demyelination, with neurodegeneration (71). In MS, activated T-cells, specific for self-antigens, such as myelin, migrate into CNS and result in axonal demyelination (96). First line therapy for patients with MS is immunosuppression/immunomodulation therapy that is generally employed with success (97). However, several patients do not respond to these therapies and relapse with neurological deterioration. Patients with relapse can benefit from allogeneic or autologous HSCT, as a viable therapeutic option. The HSCT, as a therapeutic intervention in MS treatment, was suggested in 1995 and initial results were reported beginning with 1997 (98, 99). Several studies, in both animal models of MS and clinical trials have shown that HSCT can induce MS remission and improvement (12). However, a few studies argued that HSCT has no effect on MS improvement. The EAE-diseased mice were treated with allogeneic HSCT, during the acute phase of MS, and all mice went into a complete remission and did not show relapses (100, 101). Also, autologous HSCT, in EAE mice, resulted in complete remission (102, 103). Takahashi et al. transduced TREM-2 (an innate immune receptor) in bone marrow-derived myeloid precursor cells and intravenously injected it to mice with EAE, an animal model of MS. They observed that TREM-2 transduced myeloid precursors ameliorate clinical symptom of MS in mice with EAE, by clearance of nervous tissue debris and degenerated myelin (104). Resident perivascular macrophage and microglia, in the CNS, were physiologically derived from myeloid progenitors of HSCs, during development as well as throughout life span (105-107). Moreover, it has been presented that several HSCs are recruited to sites of neurological damage, to become functional perivascular macrophage and microglia like cells (29, 108, 109). Macrophages efficiently remove cellular debris in acute injuries of the neural system. This is accompanied by amelioration of inflammation and neuroinflammatory diseases recovery (110-112). Another study evaluated clinical and neurological outcomes, after autologous HSCT in 22 patients with progressive MS. They showed that most patients with progressive MS improve after HSCT (113). The proposed mechanism for improvement of MS symptoms, by autologous HSCT is immune system alteration (114). Fassas et al. reported treatment of 15 patients with progressive MS and a median expanded disability status scale (EDSS) of 6.0 by HSCT after conditioning. During 6 months follow up, there were no death and no worsening in neurological symptoms and EDSS was improved in seven of 15 patients (98). Saiz et al. transplanted HSC on five patients with progressive MS and median EDSS of 6.5, after carmustine, cyclophosphamide and antilymphocyte globulin conditioning. They achieved improvement in four patients, revealed on MRI, whereas the neurological symptoms worsened in the fifth patients (115). Large series of MS patients, including 85 cases, were evaluated by the European Group for Blood and Marrow Transplantation (EBMT) Autoimmune Disease Working Party. Totally, 70% and 26% of patients were in secondary progressive phase and primary progressive phase of MS, respectively. The median EDSS of patients was 6.5 (ranging from 4.5 to 8.5). They were subjected for HSCT after conditioning. During a median 16 months follow up, the chance of progression-free survival was 74%, at 3 years. Five patients died from treatment related causes, including: infection and cardiac failure (116). Patients with both hematological neoplasms and autoimmune diseases inconsistently respond to HSCT. Mandalfino et al. transplanted HSC on three cases with hematological malignancy and co-existent MS. They observed that patients achieved neurological improvement, following HSCT (117). However, Lu et al. reported a case of MS associated with chronic myelogenous leukemia in a 39-year-old woman, which showed continuation of MS activity after allogeneic HSCT (118). Another study on five autopsy cases, in patients with MS that were cured by autologous HSCT, showed that MS activity continued in spite of high dose cytotoxic/immunosuppressive therapy (119). The HSCT is still in experimental therapy. However, these studies are heterogeneous in number of patients, follow up duration, status of MS symptoms in patients, conditioning regimen. However, results suggest that hematopoietic stem cell transplantation can improve MS symptoms in the progressive phase.

2.6. Embryonic Stem Cells Application in Multiple Sclerosis Treatment

The ESCs are pluripotent cells that derived from the inner cell mass of an early stage embryo, called blastocyst. They are able to differentiate into all cell types in the body. The actual limitation, in preparation of sufficient human oligodendrocyte precursor cells, orients the research towards obtaining tissue specific progenitor cells from human ESCs. Several researchers have differentiated mouse ESCs into oligodendrocyte, with myelogenic properties (120-123). Also, other groups showed that human ESCs can be directed into neural cells (124-127). In recent studies, scientists discovered several systems, such as small molecules and specific transcription factors, that control embryonic stem cells fate to produce neurons (128-131) and oligodendrocytes (132, 133). Human ESCs-derived oligodendrocytes are capable of remyelination (132, 134, 135). However, there are always the risks of tumorigenicity in neural cells derived from ESCs, which limit clinical trials (55). Especially in human, ESC-based therapies might give rise to teratomas from undifferentiated ESCs or incompletely differentiated neural cells (136, 137). Aharonowiz et al. transplanted human ESC-derived neural progenitors into mice with EAE (138). They observed that clinical symptoms of EAE were remarkably reduced after transplantation. Histological evaluation revealed that transplanted neural progenitors migrate to the mice brain, especially in host white matter. However, remyelination and production of mature oligodendrocytes were not clearly seen. They concluded that the therapeutic effect of neural progenitor’s transplantation was mediated by an immunosuppressive neuroprotective mechanism. Further studies are required to define the efficacy of ESCs-derived neural cell therapy in MS patients.

3. Results

Because NSCs can differentiate into mature oligodendrocytes and neurons, in animal models of cerebral degeneration, they are regarded as a perspective for MS. Other types of NSCs, including NSCs, BM-NSCs and NPCs, have proved their capacity of differentiation into oligodendrocytes and remyelination.

The MSCs promote repair and recovery after intrathecal injection, suggesting an influence on the rate of repair of all endogenous progenitors in spinal cords, confirmed by amelioration of EDSS.

The autologous HSCT has been proven efficient in selected cases of MS patients who do not respond to first line immunosuppression/immunomodulation therapy. The most evident responses to HSCT were seen especially in patients with relapsing MS. Nevertheless, the progressive phase of MS can also benefit from an improvement in symptomatology.

Although with the risk of development of teratomas from undifferentiated of incompletely differentiated cells, ESCs have shown a potential immunosuppression mechanism responsible for neuroprotection in cases of MS.

4. Conclusions

Nowadays, cellular therapy has opened a new paradigm in treatment of several disorders, including MS, as a neurodegenerative disease. Therefore, cell and SC transplantation have introduced promising hope in this area. On the other hand, there are several safety concerns about the clinical applications of SCs. Therefore, it is necessary to eliminate these risks before translating from the basic and experimental sciences to clinical transplantation trials. In summary, more experimental and clinical trials are needed to lead investigators in this area of research.

Acknowledgements

References

  • 1.

    Ardeshiry Lajimi A, Hagh MF, Saki N, Mortaz E, Soleimani M, Rahim F. 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. [PubMed ID: 24505515].

  • 2.

    Radaelli M, Merlini A, Greco R, Sangalli F, Comi G, Ciceri F, et al. Autologous bone marrow transplantation for the treatment of multiple sclerosis. Curr Neurol Neurosci Rep. 2014;14(9):478. [PubMed ID: 25037718]. https://doi.org/10.1007/s11910-014-0478-0.

  • 3.

    Holloman JP, Ho CC, Hukki A, Huntley JL, Gallicano GI. The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis. Am J Stem Cells. 2013;2(2):95-107. [PubMed ID: 23862098].

  • 4.

    Sahraian MA, Bonab MM, Karvigh SA, Yazdanbakhsh S, Nikbin B, Lotfi J. Intrathecal Mesenchymal Stem Cell Therapy in Multiple Sclerosis: A Follow-Up Study for Five Years After Injection. Arch Neurosci. 2014;1(2):71-5.

  • 5.

    Thelen JM, Lynch SG, Bruce AS, Hancock LM, Bruce JM. Polypharmacy in multiple sclerosis: relationship with fatigue, perceived cognition, and objective cognitive performance. J Psychosom Res. 2014;76(5):400-4. [PubMed ID: 24745782]. https://doi.org/10.1016/j.jpsychores.2014.02.013.

  • 6.

    Mohyeddin Bonab M, Mohajeri M, Sahraian MA, Yazdanifar M, Aghsaie A, Farazmand A, et al. Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells. Arch Med Res. 2013;44(4):266-72. [PubMed ID: 23684533]. https://doi.org/10.1016/j.arcmed.2013.03.007.

  • 7.

    Zafranskaya MM, Nizheharodova DB, Yurkevich MY, Lamouskaya NV, Motuzova YM, Bagatka SS, et al. In vitro assessment of mesenchymal stem cells immunosuppressive potential in multiple sclerosis patients. Immunol Lett. 2013;149(1-2):9-18. [PubMed ID: 23089549]. https://doi.org/10.1016/j.imlet.2012.10.010.

  • 8.

    Silani V, Cova L. Stem cell transplantation in multiple sclerosis: safety and ethics. J Neurol Sci. 2008;265(1-2):116-21. [PubMed ID: 17619025]. https://doi.org/10.1016/j.jns.2007.06.010.

  • 9.

    Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, et al. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 1 historical and established therapies. MS Neurology Group of the Australian and New Zealand Association of Neurologists. J Clin Neurosci. 2014;21(11):1835-46. [PubMed ID: 24993135]. https://doi.org/10.1016/j.jocn.2014.01.016.

  • 10.

    Zhao C, Zawadzka M, Roulois AJ, Bruce CC, Franklin RJ. Promoting remyelination in multiple sclerosis by endogenous adult neural stem/precursor cells: defining cellular targets. J Neurol Sci. 2008;265(1-2):12-6. [PubMed ID: 17570402]. https://doi.org/10.1016/j.jns.2007.05.008.

  • 11.

    Fassas A, Kimiskidis VK. Autologous hemopoietic stem cell transplantation in the treatment of multiple sclerosis: rationale and clinical experience. J Neurol Sci. 2004;223(1):53-8. [PubMed ID: 15261561]. https://doi.org/10.1016/j.jns.2004.04.020.

  • 12.

    Shevchenko YL, Novik AA, Kuznetsov AN, Afanasiev BV, Lisukov IA, Kozlov VA, et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Exp Hematol. 2008;36(8):922-8. [PubMed ID: 18468768]. https://doi.org/10.1016/j.exphem.2008.03.001.

  • 13.

    Keegan BM, Noseworthy JH. Multiple sclerosis. Annu Rev Med. 2002;53:285-302. [PubMed ID: 11818475]. https://doi.org/10.1146/annurev.med.53.082901.103909.

  • 14.

    Steinman L. Multiple sclerosis: a two-stage disease. Nat Immunol. 2001;2(9):762-4. [PubMed ID: 11526378]. https://doi.org/10.1038/ni0901-762.

  • 15.

    Chandran S, Compston A. Neural stem cells as a potential source of oligodendrocytes for myelin repair. J Neurol Sci. 2005;233(1-2):179-81. [PubMed ID: 15907942]. https://doi.org/10.1016/j.jns.2005.03.019.

  • 16.

    Corboy JR, Goodin DS, Frohman EM. Disease-modifying Therapies for Multiple Sclerosis. Curr Treat Options Neurol. 2003;5(1):35-54. [PubMed ID: 12521562].

  • 17.

    Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2003;348(1):15-23. [PubMed ID: 12510038]. https://doi.org/10.1056/NEJMoa020696.

  • 18.

    Teixeira MZ. Immunomodulatory drugs (natalizumab), worsening of multiple sclerosis, rebound effect and similitude. Homeopathy. 2013;102(3):215-24. [PubMed ID: 23870382]. https://doi.org/10.1016/j.homp.2013.05.001.

  • 19.

    Kremenchutzky M, O'Connor P, Hohlfeld R, Zhang-Auberson L, von Rosenstiel P, Meng X, et al. Impact of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod: Subgroup analyses of the Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study. Mult Scler Relat Disord. 2014;3(3):341-9. [PubMed ID: 25876471]. https://doi.org/10.1016/j.msard.2013.10.006.

  • 20.

    Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008;7(7):626-36. [PubMed ID: 18565456]. https://doi.org/10.1016/s1474-4422(08)70138-8.

  • 21.

    Fernandez O, Oreja-Guevara C, Arroyo R, Izquierdo G, Perez JL, Montalban X. Natalizumab treatment of multiple sclerosis in Spain: results of an extensive observational study. J Neurol. 2012;259(9):1814-23. [PubMed ID: 22289966]. https://doi.org/10.1007/s00415-012-6414-9.

  • 22.

    Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74(6):659-74. [PubMed ID: 24740824]. https://doi.org/10.1007/s40265-014-0212-x.

  • 23.

    Payne N, Siatskas C, Bernard CC. The promise of stem cell and regenerative therapies for multiple sclerosis. J Autoimmun. 2008;31(3):288-94. [PubMed ID: 18504116]. https://doi.org/10.1016/j.jaut.2008.04.002.

  • 24.

    Spain RI, Cameron MH, Bourdette D. Recent developments in multiple sclerosis therapeutics. BMC Med. 2009;7:74. [PubMed ID: 19968863]. https://doi.org/10.1186/1741-7015-7-74.

  • 25.

    Munzel EJ, Williams A. Promoting remyelination in multiple sclerosis-recent advances. Drugs. 2013;73(18):2017-29. [PubMed ID: 24242317]. https://doi.org/10.1007/s40265-013-0146-8.

  • 26.

    Keirstead HS. Stem cells for the treatment of myelin loss. Trends Neurosci. 2005;28(12):677-83. [PubMed ID: 16213602]. https://doi.org/10.1016/j.tins.2005.09.008.

  • 27.

    Pluchino S, Zanotti L, Brini E, Ferrari S, Martino G. Regeneration and repair in multiple sclerosis: the role of cell transplantation. Neurosci Lett. 2009;456(3):101-6. [PubMed ID: 19429143]. https://doi.org/10.1016/j.neulet.2008.03.097.

  • 28.

    Huang JK, Franklin RJ. Regenerative medicine in multiple sclerosis: identifying pharmacological targets of adult neural stem cell differentiation. Neurochem Int. 2011;59(3):329-32. [PubMed ID: 21300122]. https://doi.org/10.1016/j.neuint.2011.01.017.

  • 29.

    Ben-Hur T. Cell therapy for multiple sclerosis. Neurotherapeutics. 2011;8(4):625-42. [PubMed ID: 21904787]. https://doi.org/10.1007/s13311-011-0073-x.

  • 30.

    Riordan NH, Ichim TE, Min WP, Wang H, Solano F, Lara F, et al. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med. 2009;7:29. [PubMed ID: 19393041]. https://doi.org/10.1186/1479-5876-7-29.

  • 31.

    Rice CM, Kemp K, Wilkins A, Scolding NJ. Cell therapy for multiple sclerosis: an evolving concept with implications for other neurodegenerative diseases. Lancet. 2013;382(9899):1204-13. [PubMed ID: 24095194]. https://doi.org/10.1016/s0140-6736(13)61810-3.

  • 32.

    Lassmann H. Stem cell and progenitor cell transplantation in multiple sclerosis: the discrepancy between neurobiological attraction and clinical feasibility. J Neurol Sci. 2005;233(1-2):83-6. [PubMed ID: 15949497]. https://doi.org/10.1016/j.jns.2005.03.007.

  • 33.

    Rice C, Halfpenny C, Scolding N. Cell therapy in demyelinating diseases. NeuroRx. 2004;1(4):415-23. [PubMed ID: 15717045]. https://doi.org/10.1602/neurorx.1.4.415.

  • 34.

    Pluchino S, Martino G. The therapeutic plasticity of neural stem/precursor cells in multiple sclerosis. J Neurol Sci. 2008;265(1-2):105-10. [PubMed ID: 17706971]. https://doi.org/10.1016/j.jns.2007.07.020.

  • 35.

    Einstein O, Ben-Hur T. The changing face of neural stem cell therapy in neurologic diseases. Arch Neurol. 2008;65(4):452-6. [PubMed ID: 18413466]. https://doi.org/10.1001/archneur.65.4.452.

  • 36.

    Brundin L, Brismar H, Danilov AI, Olsson T, Johansson CB. Neural stem cells: a potential source for remyelination in neuroinflammatory disease. Brain Pathol. 2003;13(3):322-8. [PubMed ID: 12946021].

  • 37.

    Nait-Oumesmar B, Picard-Riera N, Kerninon C, Decker L, Seilhean D, Hoglinger GU, et al. Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors. Proc Natl Acad Sci U S A. 2007;104(11):4694-9. [PubMed ID: 17360586]. https://doi.org/10.1073/pnas.0606835104.

  • 38.

    Einstein O, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Polyzoidou E, Lavon I, et al. Transplanted neural precursor cells reduce brain inflammation to attenuate chronic experimental autoimmune encephalomyelitis. Exp Neurol. 2006;198(2):275-84. [PubMed ID: 16472805]. https://doi.org/10.1016/j.expneurol.2005.11.007.

  • 39.

    Ben-Hur T, van Heeswijk RB, Einstein O, Aharonowiz M, Xue R, Frost EE, et al. Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice. Magn Reson Med. 2007;57(1):164-71. [PubMed ID: 17191231]. https://doi.org/10.1002/mrm.21116.

  • 40.

    Ben-Hur T, Einstein O, Mizrachi-Kol R, Ben-Menachem O, Reinhartz E, Karussis D, et al. Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia. 2003;41(1):73-80. [PubMed ID: 12465047]. https://doi.org/10.1002/glia.10159.

  • 41.

    Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci. 1996;16(23):7599-609. [PubMed ID: 8922416].

  • 42.

    Einstein O, Fainstein N, Vaknin I, Mizrachi-Kol R, Reihartz E, Grigoriadis N, et al. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol. 2007;61(3):209-18. [PubMed ID: 17187374]. https://doi.org/10.1002/ana.21033.

  • 43.

    Ben-Hur T. Immunomodulation by neural stem cells. J Neurol Sci. 2008;265(1-2):102-4. [PubMed ID: 17583749]. https://doi.org/10.1016/j.jns.2007.05.007.

  • 44.

    Pluchino S, Gritti A, Blezer E, Amadio S, Brambilla E, Borsellino G, et al. Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol. 2009;66(3):343-54. [PubMed ID: 19798728]. https://doi.org/10.1002/ana.21745.

  • 45.

    Quesenberry PJ, Dooner G, Colvin G, Abedi M. Stem cell biology and the plasticity polemic. Exp Hematol. 2005;33(4):389-94. [PubMed ID: 15781328]. https://doi.org/10.1016/j.exphem.2004.11.005.

  • 46.

    Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature. 2006;441(7097):1094-6. [PubMed ID: 16810245]. https://doi.org/10.1038/nature04960.

  • 47.

    Yandava BD, Billinghurst LL, Snyder EY. "Global" cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. Proc Natl Acad Sci U S A. 1999;96(12):7029-34. [PubMed ID: 10359833].

  • 48.

    Hammang JP, Archer DR, Duncan ID. Myelination following transplantation of EGF-responsive neural stem cells into a myelin-deficient environment. Exp Neurol. 1997;147(1):84-95. [PubMed ID: 9294405]. https://doi.org/10.1006/exnr.1997.6592.

  • 49.

    Milward EA, Lundberg CG, Ge B, Lipsitz D, Zhao M, Duncan ID. Isolation and transplantation of multipotential populations of epidermal growth factor-responsive, neural progenitor cells from the canine brain. J Neurosci Res. 1997;50(5):862-71. [PubMed ID: 9418973].

  • 50.

    Kohama I, Lankford KL, Preiningerova J, White FA, Vollmer TL, Kocsis JD. Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci. 2001;21(3):944-50. [PubMed ID: 11157080].

  • 51.

    Barnett SC, Alexander CL, Iwashita Y, Gilson JM, Crowther J, Clark L, et al. Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain. 2000;123 ( Pt 8):1581-8. [PubMed ID: 10908188].

  • 52.

    Kato T, Honmou O, Uede T, Hashi K, Kocsis JD. Transplantation of human olfactory ensheathing cells elicits remyelination of demyelinated rat spinal cord. Glia. 2000;30(3):209-18. [PubMed ID: 10756071].

  • 53.

    Imaizumi T, Lankford KL, Burton WV, Fodor WL, Kocsis JD. Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord. Nat Biotechnol. 2000;18(9):949-53. [PubMed ID: 10973214]. https://doi.org/10.1038/79432.

  • 54.

    Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003;422(6933):688-94. [PubMed ID: 12700753]. https://doi.org/10.1038/nature01552.

  • 55.

    Magalon K, Cantarella C, Monti G, Cayre M, Durbec P. Enriched environment promotes adult neural progenitor cell mobilization in mouse demyelination models. Eur J Neurosci. 2007;25(3):761-71. [PubMed ID: 17298600]. https://doi.org/10.1111/j.1460-9568.2007.05335.x.

  • 56.

    Karussis D, Kassis I, Kurkalli BG, Slavin S. 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;265(1-2):131-5. [PubMed ID: 17610906]. https://doi.org/10.1016/j.jns.2007.05.005.

  • 57.

    Zhang J, Li Y, Chen J, Cui Y, Lu M, Elias SB, et al. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol. 2005;195(1):16-26. [PubMed ID: 15904921]. https://doi.org/10.1016/j.expneurol.2005.03.018.

  • 58.

    Pluchino S, Zanotti L, Brambilla E, Rovere-Querini P, Capobianco A, Alfaro-Cervello C, et al. Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function. PLoS One. 2009;4(6). eee5959. [PubMed ID: 19543526]. https://doi.org/10.1371/journal.pone.0005959.

  • 59.

    Makar TK, Trisler D, Sura KT, Sultana S, Patel N, Bever CT. Brain derived neurotrophic factor treatment reduces inflammation and apoptosis in experimental allergic encephalomyelitis. J Neurol Sci. 2008;270(1-2):70-6. [PubMed ID: 18374360]. https://doi.org/10.1016/j.jns.2008.02.011.

  • 60.

    Portmann-Lanz CB, Schoeberlein A, Portmann R, Mohr S, Rollini P, Sager R, et al. Turning placenta into brain: placental mesenchymal stem cells differentiate into neurons and oligodendrocytes. Am J Obstet Gynecol. 2010;202(3):2940-29400000000000. [PubMed ID: 20060088]. https://doi.org/10.1016/j.ajog.2009.10.893.

  • 61.

    Lue J, Lin G, Ning H, Xiong A, Lin CS, Glenn JS. Transdifferentiation of adipose-derived stem cells into hepatocytes: a new approach. Liver Int. 2010;30(6):913-22. [PubMed ID: 20353420]. https://doi.org/10.1111/j.1478-3231.2010.02231.x.

  • 62.

    Zhang Q, Shi S, Liu Y, Uyanne J, Shi Y, Shi S, et al. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol. 2009;183(12):7787-98. [PubMed ID: 19923445]. https://doi.org/10.4049/jimmunol.0902318.

  • 63.

    Saki N, Abroun S, Farshdousti Hagh M, Asgharei F. Neoplastic bone marrow niche: hematopoietic and mesenchymal stem cells. Cell J. 2011;13(3):131-6. [PubMed ID: 23508881].

  • 64.

    Jackson WM, Nesti LJ, Tuan RS. Potential therapeutic applications of muscle-derived mesenchymal stem and progenitor cells. Expert Opin Biol Ther. 2010;10(4):505-17. [PubMed ID: 20218920]. https://doi.org/10.1517/14712591003610606.

  • 65.

    Dehghani Fard A, Saki N, Ahmadvand M, Mahmoodinia Maymand M, Mosahebi Mohammadi M, Soleimani M. Mesenchymal Stem Cell; Biology, Application and Its Role in Regenerative Medicine. Sci J Blood Transfus Organ. 2012;8(4):306-20.

  • 66.

    Krampera M, Sartoris S, Liotta F, Pasini A, Angeli R, Cosmi L, et al. Immune regulation by mesenchymal stem cells derived from adult spleen and thymus. Stem Cells Dev. 2007;16(5):797-810. [PubMed ID: 17999601]. https://doi.org/10.1089/scd.2007.0024.

  • 67.

    Reger RL, Tucker AH, Wolfe MR. Differentiation and characterization of human MSCs. Methods Mol Biol. 2008;449:93-107. [PubMed ID: 18370086]. https://doi.org/10.1007/978-1-60327-169-1_7.

  • 68.

    Delorme B, Nivet E, Gaillard J, Haupl T, Ringe J, Deveze A, et al. The human nose harbors a niche of olfactory ectomesenchymal stem cells displaying neurogenic and osteogenic properties. Stem Cells Dev. 2010;19(6):853-66. [PubMed ID: 19905894]. https://doi.org/10.1089/scd.2009.0267.

  • 69.

    in 't Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, et al. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica. 2003;88(8):845-52. [PubMed ID: 12935972].

  • 70.

    Dazzi F, Krampera M. Mesenchymal stem cells and autoimmune diseases. Best Pract Res Clin Haematol. 2011;24(1):49-57. [PubMed ID: 21396592]. https://doi.org/10.1016/j.beha.2011.01.002.

  • 71.

    Frohman EM, Racke MK, Raine CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med. 2006;354(9):942-55. [PubMed ID: 16510748]. https://doi.org/10.1056/NEJMra052130.

  • 72.

    Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol. 2011;10(7):649-56. [PubMed ID: 21683930]. https://doi.org/10.1016/s1474-4422(11)70121-1.

  • 73.

    Cohen JA. Mesenchymal stem cell transplantation in multiple sclerosis. J Neurol Sci. 2013;333(1-2):43-9. [PubMed ID: 23294498]. https://doi.org/10.1016/j.jns.2012.12.009.

  • 74.

    Slavin S, Kurkalli BG, Karussis D. The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders. Clin Neurol Neurosurg. 2008;110(9):943-6. [PubMed ID: 18325660]. https://doi.org/10.1016/j.clineuro.2008.01.014.

  • 75.

    Gregory CA, Prockop DJ, Spees JL. Non-hematopoietic bone marrow stem cells: molecular control of expansion and differentiation. Exp Cell Res. 2005;306(2):330-5. [PubMed ID: 15925588]. https://doi.org/10.1016/j.yexcr.2005.03.018.

  • 76.

    Harris VK, Yan QJ, Vyshkina T, Sahabi S, Liu X, Sadiq SA. Clinical and pathological effects of intrathecal injection of mesenchymal stem cell-derived neural progenitors in an experimental model of multiple sclerosis. J Neurol Sci. 2012;313(1-2):167-77. [PubMed ID: 21962795]. https://doi.org/10.1016/j.jns.2011.08.036.

  • 77.

    Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67(10):1187-94. [PubMed ID: 20937945]. https://doi.org/10.1001/archneurol.2010.248.

  • 78.

    Yamout B, Hourani R, Salti H, Barada W, El-Hajj T, Al-Kutoubi A, et al. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol. 2010;227(1-2):185-9. [PubMed ID: 20728948]. https://doi.org/10.1016/j.jneuroim.2010.07.013.

  • 79.

    Zhang YJ, Zhang W, Lin CG, Ding Y, Huang SF, Wu JL, et al. Neurotrophin-3 gene modified mesenchymal stem cells promote remyelination and functional recovery in the demyelinated spinal cord of rats. J Neurol Sci. 2012;313(1-2):64-74. [PubMed ID: 21996274]. https://doi.org/10.1016/j.jns.2011.09.027.

  • 80.

    Bonab MM, Sahraian MA, Aghsaie A, Karvigh SA, Hosseinian SM, Nikbin B, et al. Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr Stem Cell Res Ther. 2012;7(6):407-14. [PubMed ID: 23061813].

  • 81.

    Rice CM, Mallam EA, Whone AL, Walsh P, Brooks DJ, Kane N, et al. Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis. Clin Pharmacol Ther. 2010;87(6):679-85. [PubMed ID: 20445531]. https://doi.org/10.1038/clpt.2010.44.

  • 82.

    Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-6. [PubMed ID: 22236384]. https://doi.org/10.1016/s1474-4422(11)70305-2.

  • 83.

    Connick P, Kolappan M, Patani R, Scott MA, Crawley C, He XL, et al. 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. [PubMed ID: 21366911]. https://doi.org/10.1186/1745-6215-12-62.

  • 84.

    Harris VK, Faroqui R, Vyshkina T, Sadiq SA. 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;1(7):536-47. [PubMed ID: 23197858]. https://doi.org/10.5966/sctm.2012-0015.

  • 85.

    Odinak MM, Bisaga GN, Novitskiĭ AV, Tyrenko VV, Fominykh MS, Bilibina AA, et al. Transplantation of Mesenchymal Stem Cells in Multiple Sclerosis. Zh Nevrol Psikhiatr Im S S Korsakova. 2010;111(2 Pt 2):72-6.

  • 86.

    Mohajeri M, Farazmand A, Mohyeddin Bonab M, Nikbin B, Minagar A. FOXP3 gene expression in multiple sclerosis patients pre- and post mesenchymal stem cell therapy. Iran J Allergy Asthma Immunol. 2011;10(3):155-61. [PubMed ID: 21891821].

  • 87.

    Darlington PJ, Boivin MN, Renoux C, Francois M, Galipeau J, Freedman MS, et al. Reciprocal Th1 and Th17 regulation by mesenchymal stem cells: Implication for multiple sclerosis. Ann Neurol. 2010;68(4):540-5. [PubMed ID: 20661924]. https://doi.org/10.1002/ana.22065.

  • 88.

    Liang J, Zhang H, Hua B, Wang H, Wang J, Han Z, et al. Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis. Mult Scler. 2009;15(5):644-6. [PubMed ID: 19389752]. https://doi.org/10.1177/1352458509104590.

  • 89.

    Mohyeddin Bonab M, Yazdanbakhsh S, Lotfi J, Alimoghaddom K, Talebian F, Hooshmand F, et al. Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iran J Immunol. 2007;4(1):50-7. [PubMed ID: 17652844].

  • 90.

    Lublin FD, Bowen JD, Huddlestone J, Kremenchutzky M, Carpenter A, Corboy JR, et al. Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study. Mult Scler Relat Disord. 2014;3(6):696-704. [PubMed ID: 25891548]. https://doi.org/10.1016/j.msard.2014.08.002.

  • 91.

    Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014;124(3):1168-72. [PubMed ID: 24531550]. https://doi.org/10.1172/JCI71691.

  • 92.

    Pasquini MC, Griffith LM, Arnold DL, Atkins HL, Bowen JD, Chen JT, et al. Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies. Biol Blood Marrow Transplant. 2010;16(8):1076-83. [PubMed ID: 20304084]. https://doi.org/10.1016/j.bbmt.2010.03.012.

  • 93.

    Atkins HL, Freedman MS. Hematopoietic stem cell therapy for multiple sclerosis: top 10 lessons learned. Neurotherapeutics. 2013;10(1):68-76. [PubMed ID: 23192675]. https://doi.org/10.1007/s13311-012-0162-5.

  • 94.

    Blanco Y, Saiz A, Carreras E, Graus F. Autologous haematopoietic-stem-cell transplantation for multiple sclerosis. Lancet Neurol. 2005;4(1):54-63. [PubMed ID: 15620857]. https://doi.org/10.1016/s1474-4422(04)00966-4.

  • 95.

    Burt RK, Loh Y, Cohen B, Stefoski D, Balabanov R, Katsamakis G, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8(3):244-53. [PubMed ID: 19186105]. https://doi.org/10.1016/s1474-4422(09)70017-1.

  • 96.

    Tabatabai G, Bahr O, Mohle R, Eyupoglu IY, Boehmler AM, Wischhusen J, et al. Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells. Brain. 2005;128(Pt 9):2200-11. [PubMed ID: 15947066]. https://doi.org/10.1093/brain/awh563.

  • 97.

    McCormack PL, Scott LJ. Interferon-beta-1b: a review of its use in relapsing-remitting and secondary progressive multiple sclerosis. CNS Drugs. 2004;18(8):521-46. [PubMed ID: 15182221].

  • 98.

    Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant. 1997;20(8):631-8. [PubMed ID: 9383225]. https://doi.org/10.1038/sj.bmt.1700944.

  • 99.

    Burt RK, Traynor AE, Cohen B, Karlin KH, Davis FA, Stefoski D, et al. T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients. Bone Marrow Transplant. 1998;21(6):537-41. [PubMed ID: 9543056]. https://doi.org/10.1038/sj.bmt.1701129.

  • 100.

    van Bekkum DW. Stem cell transplantation for autoimmune disorders. Preclinical experiments. Best Pract Res Clin Haematol. 2004;17(2):201-22. [PubMed ID: 15302335]. https://doi.org/10.1016/j.beha.2004.04.003.

  • 101.

    van Gelder M, van Bekkum DW. Treatment of relapsing experimental autoimmune encephalomyelitis in rats with allogeneic bone marrow transplantation from a resistant strain. Bone Marrow Transplant. 1995;16(3):343-51. [PubMed ID: 8535305].

  • 102.

    van Gelder M, Kinwel-Bohre EP, van Bekkum DW. Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT. Bone Marrow Transplant. 1993;11(3):233-41. [PubMed ID: 8467289].

  • 103.

    van Gelder M, van Bekkum DW. Effective treatment of relapsing experimental autoimmune encephalomyelitis with pseudoautologous bone marrow transplantation. Bone Marrow Transplant. 1996;18(6):1029-34. [PubMed ID: 8971369].

  • 104.

    Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 2007;4(4). eee124. [PubMed ID: 17425404]. https://doi.org/10.1371/journal.pmed.0040124.

  • 105.

    Hickey WF, Kimura H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science. 1988;239(4837):290-2. [PubMed ID: 3276004].

  • 106.

    Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med. 2001;7(12):1356-61. [PubMed ID: 11726978]. https://doi.org/10.1038/nm1201-1356.

  • 107.

    Simard AR, Rivest S. Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. Faseb j. 2004;18(9):998-1000. [PubMed ID: 15084516]. https://doi.org/10.1096/fj.04-1517fje.

  • 108.

    Flugel A, Bradl M, Kreutzberg GW, Graeber MB. Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy. J Neurosci Res. 2001;66(1):74-82. [PubMed ID: 11599003].

  • 109.

    Bechmann I, Goldmann J, Kovac AD, Kwidzinski E, Simburger E, Naftolin F, et al. Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia. Faseb j. 2005;19(6):647-9. [PubMed ID: 15671154]. https://doi.org/10.1096/fj.04-2599fje.

  • 110.

    Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature. 1997;390(6658):350-1. [PubMed ID: 9389474]. https://doi.org/10.1038/37022.

  • 111.

    Savill J, Dransfield I, Gregory C, Haslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2002;2(12):965-75. [PubMed ID: 12461569]. https://doi.org/10.1038/nri957.

  • 112.

    Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6(12):1191-7. [PubMed ID: 16369558]. https://doi.org/10.1038/ni1276.

  • 113.

    Xu J, Ji BX, Su L, Dong HQ, Sun XJ, Liu CY. Clinical outcomes after autologous haematopoietic stem cell transplantation in patients with progressive multiple sclerosis. Chin Med J (Engl). 2006;119(22):1851-5. [PubMed ID: 17134581].

  • 114.

    Tyndall A, Matucci-Cerinic M. Haematopoietic stem cell transplantation for the treatment of systemic sclerosis and other autoimmune disorders. Expert Opin Biol Ther. 2003;3(7):1041-9. [PubMed ID: 14519069]. https://doi.org/10.1517/14712598.3.7.1041.

  • 115.

    Saiz A, Carreras E, Berenguer J, Yague J, Martinez C, Marin P, et al. MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS. Neurology. 2001;56(8):1084-9. [PubMed ID: 11320183].

  • 116.

    Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E, et al. Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249(8):1088-97. [PubMed ID: 12195460]. https://doi.org/10.1007/s00415-002-0800-7.

  • 117.

    Mandalfino P, Rice G, Smith A, Klein JL, Rystedt L, Ebers GC. Bone marrow transplantation in multiple sclerosis. J Neurol. 2000;247(9):691-5. [PubMed ID: 11081808].

  • 118.

    Lu JQ, Storek J, Metz L, Yong VW, Stevens AM, Nash RA, et al. Continued disease activity in a patient with multiple sclerosis after allogeneic hematopoietic cell transplantation. Arch Neurol. 2009;66(1):116-20. [PubMed ID: 19139309]. https://doi.org/10.1001/archneurol.2008.522.

  • 119.

    Gualandi F, Bruno B, Van Lint MT, Luchetti S, Uccelli A, Capello E, et al. Autologous stem cell transplantation for severe autoimmune diseases: a 10-year experience. Ann N Y Acad Sci. 2007;1110:455-64. [PubMed ID: 17911461]. https://doi.org/10.1196/annals.1423.048.

  • 120.

    Brustle O, Jones KN, Learish RD, Karram K, Choudhary K, Wiestler OD, et al. Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science. 1999;285(5428):754-6. [PubMed ID: 10427001].

  • 121.

    Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF, et al. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc Natl Acad Sci U S A. 2000;97(11):6126-31. [PubMed ID: 10823956].

  • 122.

    Billon N, Jolicoeur C, Ying QL, Smith A, Raff M. Normal timing of oligodendrocyte development from genetically engineered, lineage-selectable mouse ES cells. J Cell Sci. 2002;115(Pt 18):3657-65. [PubMed ID: 12186951].

  • 123.

    Chen L, Coleman R, Leang R, Tran H, Kopf A, Walsh CM, et al. Human neural precursor cells promote neurologic recovery in a viral model of multiple sclerosis. Stem Cell Reports. 2014;2(6):825-37. [PubMed ID: 24936469]. https://doi.org/10.1016/j.stemcr.2014.04.005.

  • 124.

    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145-7. [PubMed ID: 9804556].

  • 125.

    Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000;18(4):399-404. [PubMed ID: 10748519]. https://doi.org/10.1038/74447.

  • 126.

    Reubinoff BE, Itsykson P, Turetsky T, Pera MF, Reinhartz E, Itzik A, et al. Neural progenitors from human embryonic stem cells. Nat Biotechnol. 2001;19(12):1134-40. [PubMed ID: 11731782]. https://doi.org/10.1038/nbt1201-1134.

  • 127.

    Zhang SC, Wernig M, Duncan ID, Brustle O, Thomson JA. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol. 2001;19(12):1129-33. [PubMed ID: 11731781]. https://doi.org/10.1038/nbt1201-1129.

  • 128.

    Li XJ, Hu BY, Jones SA, Zhang YS, Lavaute T, Du ZW, et al. Directed differentiation of ventral spinal progenitors and motor neurons from human embryonic stem cells by small molecules. Stem Cells. 2008;26(4):886-93. [PubMed ID: 18238853]. https://doi.org/10.1634/stemcells.2007-0620.

  • 129.

    Martinat C, Bacci JJ, Leete T, Kim J, Vanti WB, Newman AH, et al. Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc Natl Acad Sci U S A. 2006;103(8):2874-9. [PubMed ID: 16477036]. https://doi.org/10.1073/pnas.0511153103.

  • 130.

    Pomp O, Brokhman I, Ben-Dor I, Reubinoff B, Goldstein RS. Generation of peripheral sensory and sympathetic neurons and neural crest cells from human embryonic stem cells. Stem Cells. 2005;23(7):923-30. [PubMed ID: 15883233]. https://doi.org/10.1634/stemcells.2005-0038.

  • 131.

    Lee G, Kim H, Elkabetz Y, Al Shamy G, Panagiotakos G, Barberi T, et al. Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells. Nat Biotechnol. 2007;25(12):1468-75. [PubMed ID: 18037878]. https://doi.org/10.1038/nbt1365.

  • 132.

    Izrael M, Zhang P, Kaufman R, Shinder V, Ella R, Amit M, et al. Human oligodendrocytes derived from embryonic stem cells: Effect of noggin on phenotypic differentiation in vitro and on myelination in vivo. Mol Cell Neurosci. 2007;34(3):310-23. [PubMed ID: 17196394]. https://doi.org/10.1016/j.mcn.2006.11.008.

  • 133.

    Hu BY, Du ZW, Li XJ, Ayala M, Zhang SC. Human oligodendrocytes from embryonic stem cells: conserved SHH signaling networks and divergent FGF effects. Development. 2009;136(9):1443-52. [PubMed ID: 19363151]. https://doi.org/10.1242/dev.029447.

  • 134.

    Fazeli AS, Nasrabadi D, Pouya A, Mirshavaladi S, Sanati MH, Baharvand H, et al. Proteome analysis of post-transplantation recovery mechanisms of an EAE model of multiple sclerosis treated with embryonic stem cell-derived neural precursors. J Proteomics. 2013;94:437-50. [PubMed ID: 23791935]. https://doi.org/10.1016/j.jprot.2013.06.008.

  • 135.

    Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia. 2005;49(3):385-96. [PubMed ID: 15538751]. https://doi.org/10.1002/glia.20127.

  • 136.

    Hentze H, Graichen R, Colman A. Cell therapy and the safety of embryonic stem cell-derived grafts. Trends Biotechnol. 2007;25(1):24-32. [PubMed ID: 17084475]. https://doi.org/10.1016/j.tibtech.2006.10.010.

  • 137.

    Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S, et al. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron. 2006;51(2):187-99. [PubMed ID: 16846854]. https://doi.org/10.1016/j.neuron.2006.06.012.

  • 138.

    Aharonowiz M, Einstein O, Fainstein N, Lassmann H, Reubinoff B, Ben-Hur T. Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis. PLoS One. 2008;3(9). eee3145. [PubMed ID: 18773082]. https://doi.org/10.1371/journal.pone.0003145.