The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia/macrophages, which can be polarized to distinct functional phenotypes: proinflammatory (M1) or anti-inflammatory/immunoregulatory (M2). Here we show that a switch from an M1-to M2-dominant response occurred within microglia and peripherally-derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 conditioned media, and impaired in vivo following intra-lesional M2 depletion. M2 densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger animal, and in MS lesions that normally show remyelination. Blocking M2-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Our results therefore show that M2 polarization is essential for efficient remyelination and identify activin-A as a novel therapeutic target for CNS regeneration.Remyelination, the formation of myelin sheaths around demyelinated axons by newly differentiated oligodendrocytes, can occur efficiently following central nervous system (CNS) demyelination. A major component of this regenerative process is a robust innate immune response consisting of peripherally-derived macrophages and their CNS-resident counterparts, microglia. Although these microglia/macrophages are implicated in CNS autoimmune disease via secretion of toxic molecules 1 and antigen presentation to cytotoxic lymphocytes 2 , they also exhibit regenerative properties through the phagocytosis of myelin debris 3, 4 and secretion of growth/neurotrophic factors 5 . Regenerative properties of Corresponding author: Veronique E. Miron, MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh, EH16 4UU, Tel: +44 (0) 131 651 9570, Fax: +44 (0) 131 651 9501, vmiron@staffmail.ed.ac.uk. Author Contributions: V.M. conceived the project, designed and carried out experiments, performed data acquisition, quantification, and analysis, and wrote the manuscript; A.B. and A.W. assisted in in vivo studies, and A.W. assisted in data interpretation; J.-W.Z. contributed to analysis and quantification of parabiosis lesion tissue; A.B., A.W., T.Y., and P.v.W. performed lesioning experiments to provide lesion tissue and assisted in tissue selection; J.R., J.S., A.J.W, R.J.M.F. provided parabiosis lesion tissue; R.J.M.F. assisted in study design, data interpretation, and manuscript writing; C.ff.-C. supervised the project, assisted in study design, data interpretation, figure preparation, and writing of the manuscript. Europe PMC Funders GroupAuthor Manuscript Nat Neurosci. Author manuscript; available in PMC 2014 April 07. Published in final edited form as:Nat Neurosci. 2013 September ; 16(9): 1211-1218. doi:10.1038/nn.3469. Europe PMC Funders Author Manus...
Impaired function/differentiation of progenitor cells might provide an explanation for the limited remyelination observed in the majority of chronic multiple sclerosis lesions. Here, we establish that in the normal adult human CNS, the transcription factors Nkx2.2 and Olig2 are strongly expressed in progenitor cells while mature oligodendrocytes are characterized by low levels of Olig2 or Nkx2.2. In vitro studies confirmed the expression of Olig2 in oligodendroglial progenitor cells and mature oligodendrocytes while astrocytes, microglial cells and neurons were negative for Olig2. In early multiple sclerosis lesions, we found Olig2-positive progenitor cells throughout all lesion stages and in periplaque white matter (PPWM). The number of progenitors in PPWM was significantly increased compared with the white matter from controls. In chronic multiple sclerosis lesions progenitor cells were still present, however, in significantly lower numbers than in early multiple sclerosis lesions. A subpopulation of progenitor cells in early multiple sclerosis lesions and PPWM but not in control cases co-expressed NogoA, a marker of mature oligodendrocytes. The co-expression of these two markers suggested that these cells were maturing oligodendrocytes recently recruited from the progenitor pool. In contrast, in chronic multiple sclerosis lesions maturing progenitors were only rarely present. In summary, we provide evidence that a differentiation block of oligodendroglial progenitors is a major determinant of remyelination failure in chronic multiple sclerosis lesions.
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