Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes.
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.
Talbott
Jason F
JF
The MD/PhD Program, University of Louisville, Louisville, KY 40292, USA.
Loy
David N
DN
Liu
Ying
Y
Qiu
Mengsheng S
MS
Bunge
Mary Bartlett
MB
Rao
Mahendra S
MS
Whittemore
Scott R
SR
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D051792:Basic Helix-Loop-Helix Proteins; D002450:Cell Communication / Q000502:physiology; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004996:Ethidium; D005260:Female; D005786:Gene Expression Regulation; D006609:High Mobility Group Proteins / Q000096:biosynthesis; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000096:biosynthesis; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009498:Neurotoxins; D009836:Oligodendroglia / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D011916:Rats, Inbred F344; D055748:SOXB1 Transcription Factors; D012583:Schwann Cells / Q000502:physiology / Q000648:ultrastructure; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013234:Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D014157:Transcription Factors / Q000096:biosynthesis; D029961:Zebrafish Proteins
D000943:Antigens, Differentiation; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D004996:Ethidium; D006609:High Mobility Group Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715628:Nkx2-2 protein, rat; C490908:Sox1 protein, rat; C000715630:nkx2.2b protein, zebrafish