CNS-Resident Glial Progenitor/Stem Cells Produce Schwann Cells as well as Oligodendrocytes during Repair of CNS Demyelination

Abstract

After central nervous system (CNS) demyelination-such as occurs during multiple sclerosis-there is often spontaneous regeneration of myelin sheaths, mainly by oligodendrocytes but also by Schwann cells. The origins of the remyelinating cells have not previously been established. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes. These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system.

Remyelination reporter reveals prolonged refinement of spontaneously regenerated myelin

“…(i) Remyelinating cells were specifically targeted by a combination of the NG2 promoter (31) and a retrovirus that integrates DNA into the host genome only during mitosis (32). We chose the NG2 promoter because it is expressed by resident glial progenitors that can produce OLs and Schwann cells (SCs) after injury as well as by infiltrating peripheral SCs that participate in central remyelination (10,(33)(34)(35). The promoter and its efficient targeting of NG2 + glial progenitors has been fully characterized previously (31).…”

“…Postmitotic oligodendrocytes (OLs) do not readily participate in remyelination (5,6). Instead, glial progenitors, distinguished by expression of the α-receptor for PDGF and the chondroitin sulfate proteoglycan neural/glial antigen 2 (NG2) proliferate following demyelination and differentiate into remyelinating cells within a few weeks (7)(8)(9)(10). Regeneration of myelin membranes restores saltatory conduction and supports axonal integrity, leading to partial recovery of function (3,4,11,12).…”

Cell Therapy for Multiple Sclerosis

“…Tissue OPCs expressing NG2 and platelet-derived growth factor receptor-α on their cell surface are mobilized in response to demyelination [49,[51][52][53]. Recent studies provided the definitive proof that these cells are indeed the main remyelinating cell in the CNS following a demyelinating injury [54,55]. In addition, neural precursor cells (NPCs) of the adult SVZ expressing the embryonic polysialylated form of the neural cell adhesion molecule (PSA-NCAM) react to inflammation and demyelination with proliferation, and migration into the tissue and glial differentiation, generating both astrocytes and remyelinating oligodendrocytes [56][57][58][59].…”

Expression of the transcription factor Olig2 in proliferating cells in the adult zebrafish telencephalon

“…OPCs are the major dividing cell population in the adult brain of mammals (Dawson et al, 2003;Geha et al, 2009). In addition, they were shown to act as multipotent stem cells in vitro (Kondo and Raff, 2000;Nunes et al, 2003) and in vivo (Rivers et al, 2008;Zawadzka et al, 2010), which makes them interesting candidates for therapeutic applications in neurodegenerative diseases. Recent data suggest that the SVZ, similar to its generation of neurons for the olfactory bulbs via transit amplifying progenitors, can also generate new OPCs (Marshall et al, 2005;Menn et al, 2006).…”