Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes

Abstract

Chronic demyelination is a pathophysiologic component of compressive spinal cord injury (SCI) and a characteristic finding in demyelinating diseases including multiple sclerosis (MS). A better characterization of endogenous cells responsible for successful remyelination is essential for designing therapeutic strategies aimed at restoring functional myelin. The present study examined the spatiotemporal response of endogenous oligodendrocyte precursor cells (OPCs) following ethidium bromide (EB)-induced demyelination of the adult rat spinal cord. Beginning at 2 days post-EB injection (dpi), a robust mobilization of highly proliferative NG2(+) cells within the lesion was observed, none of which expressed the oligodendrocyte lineage-associated transcription factor Nkx2.2. At 7 dpi, a significant up-regulation of Nkx2.2 by OPCs within the lesion was observed, 90% of which coexpressed NG2 and virtually all of which coexpressed the bHLH transcription factor Olig2. Despite successful recruitment of Nkx2.2(+)/Olig2(+) OPCs within the lesion, demyelinated axons were not remyelinated by these OPCs in regions lacking astrocytes. Rather, Schwann cell remyelination predominated throughout the central core of the lesion, particularly around blood vessels. Oligodendrocyte remyelination was observed in the astrogliotic perimeter, suggesting a necessary role for astrocytes in oligodendrocyte maturation. In addition, reexpression of the radial glial antigen, RC-1, by reactive astrocytes and ependymal cells was observed following injury. However, these cells did not express the neural stem cell (NSC)-associated transcription factors Sox1 or Sox2, suggesting that the endogenous response is primarily mediated by glial progenitors. In vivo electrophysiology demonstrated a limited and unsustained functional recovery concurrent with endogenous remyelination following EB-induced lesions.

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

“…On the contrary, in the absence of testosterone or a functional AR, astrocytes remained sparse and P0 + myelin was preferentially detected within the lesion. This observation is consistent with previous studies showing that Schwann cell remyelination occurs in areas of the CNS where astrocytes are absent (9,10).…”

“…Thus, within a demyelinated lesion, oligodendrocyte remyelination occurs in regions where astrocytes are present, whereas Schwann cell remyelination preferentially occurs in the absence of astrocytes (7,9,10). Moreover, reducing astrocyte activation by a conditional genetic deletion promoted Schwann cell remyelination (1).…”

Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells

“…This observation is consistent with previous findings that epigenetic signals promoting the differentiation of Nurr1-expressing precursors may emanate from neighboring astrocytes (28). In fact, the role of the astrocyte in directing neurogenesis (15), mediating rescue (14), and potentiating the function of other neural cells is becoming increasingly appreciated (29). In particular, GDNF (one of possibly several natural products of the astrocytic progeny of these hNSCs) shows developmental, trophic, and protective support of DA neurons and promotes effective processing and release of DA (21)(22)(23).…”

Region-specific Differentiation Potential of Adult Rat Spinal Cord Neural Stem/Precursors and Their Plasticity in Response to In Vitro Manipulation

“…Astrocytes aid remyelination by releasing leukemia inhibitory factor, which stimulates myelination by oligodendrocytes (Ishibashi et al 2006). Whittemore and colleagues showed that in the absence of astrocytes, endogenous OPCs failed to remyelinate the injured spinal cord (Talbott et al 2005). Thus, NSPCs that differentiate into astrocytes may be useful for enhancing recovery after SCI.…”