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Myelin regeneration in multiple sclerosis: targeting endogenous stem cells.

ABSTRACT: Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

SUBMITTER: Huang JK

PROVIDER: S-EPMC3250284 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Myelin regeneration in multiple sclerosis: targeting endogenous stem cells.

Huang Jeffrey K JK Fancy Stephen P J SP Zhao Chao C Rowitch David H DH Ffrench-Constant Charles C Franklin Robin J M RJ

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20111001 4

Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelina ...[more]

PMID: 21904791

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Harnessing endogenous stem/progenitor cells for tendon regeneration.

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| S-EPMC4563693 | biostudies-literature

The monoclonal antibody GNbAC1: targeting human endogenous retroviruses in multiple sclerosis.

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| S-EPMC6407165 | biostudies-literature

Atacicept: targeting B cells in multiple sclerosis.

Project description:Multiple sclerosis (MS) has traditionally been considered to be a T-cell-mediated disease. However, there is an increasing body of evidence for the involvement of B cells and autoantibodies in the pathology of this disease, providing a rationale for treatments directed against B cells. In this paper we summarize evidence for the key role of B cells in the immunopathology of MS and review data supporting the use of a novel B-cell targeted therapy, atacicept, in this condition. Atacicept is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B-cell maturation, function and survival. Atacicept has shown selective effects on cells of the B-cell lineage, acting on mature B cells and blocking plasma cells and late stages of B-cell development while sparing B-cell progenitors and memory cells. The efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. Clinical studies were initiated to investigate the safety, tolerability and efficacy of atacicept in patients with MS. An unexpected increase in inflammatory activity in one of the trials, however, led to suspension of all atacicept trials in MS.

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Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes.

Project description:ObjectiveMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Myeloid phagocytes, including blood monocytes recruited to demyelinating lesions, may play a dual role in MS: on one hand, they might enhance CNS damage after differentiating toward a proinflammatory phenotype; on the other, they promote remyelination and repair through effective phagocytosis of myelin debris. We have previously determined that the retinoid X receptor (RXR) plays an important role in monocyte phagocytosis of myelin. Peroxisome proliferator-activated receptor γ is an RXR binding partner that plays a key role in myeloid cell biology and is targeted by the thiazolidinedione group of antidiabetics such as pioglitazone. Consequently, the purpose of this study was to determine if monocyte functions and differentiation profiles differ in MS patients compared to healthy volunteers (HV) and whether pioglitazone can reverse these differences to promote CNS recovery.MethodsMonocytes were isolated from MS patients and HV (n ≥ 36/group), and their ability to phagocytose myelin and modulate inflammation in the presence/absence of 1 μmol/L pioglitazone (the in vivo achievable concentration) was quantified by flow cytometry, transcriptional profiling, and proteomic assays.ResultsMS monocytes display impaired phagocytosis of myelin debris and enhanced proinflammatory differentiation. Pioglitazone treatment causes partial normalization of identified monocyte abnormalities in MS and fully reverses the deficit in myelin phagocytosis.InterpretationThese findings suggest that by inhibiting proinflammatory differentiation of monocytes and enhancing their phagocytosis of myelin, pioglitazone may be a useful adjunct therapy to immunomodulatory agents that target dysregulated adaptive immunity in MS.

| S-EPMC4693592 | biostudies-literature

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Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis.

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Myelin recovery in multiple sclerosis: the challenge of remyelination.

Project description:Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination-with emphasis upon myelin composition/ architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

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Multiple sclerosis: getting personal with induced pluripotent stem cells.

Project description:Human induced pluripotent stem (iPS) cells can be derived from lineage-restricted cells and represent an important tool to develop novel patient-specific cell therapies and research models for inherited and acquired diseases. Recently, patient-derived iPS cells, containing donor genetic background, have offered a breakthrough approach to study human genetics of neurodegenerative diseases. By offering an unlimited source of patient-specific disease-relevant cells, iPS cells hold great promise for understanding disease mechanisms, identifying molecular targets and developing phenotypic screens for drug discovery. This review will discuss the potential impact of using iPS cell-derived models in multiple sclerosis (MS) research and highlight some of the current challenges and prospective for generating novel therapeutic treatments for MS patients.

| S-EPMC4650727 | biostudies-other

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