Spinal cord injury (SCI) results in demyelination and loss of oligodendrocytes (OLs), the myelinating cells of the central nervous system (CNS). However, the adult CNS has a population of endogenous oligodendrocyte progenitor cells (OPC) identified by NG2 expression, which following proliferation, can give rise to myelinating oligodendrocytes. Previously, our laboratory showed that OPCs undergo enhanced proliferation following SCI. To better understand the role of OPCs following SCI and the possibility that they differentiate into oligodendrocytes, better characterization of the proliferation and fate of these OPCs after spinal trauma is needed. Also, since tissue adjacent to lesion cavities is exposed to different mediators compared to outlying spared tissue, we used a rat SCI model to compare NG2 cell proliferation and OL genesis adjacent to lesion cavities with that in spared tissue closer to meninges. NG2 cells proliferated throughout the first week post-injury and accumulated along lesion borders, especially within gray matter. By 3d post-injury (dpi), new OLs were detected throughout the cross-sections; between 4-7dpi, however, oligogenesis was restricted to lesion borders. New OLs derived from cells proliferating during 1-7dpi increased dramatically by 14dpi; most were located along lesion borders and in spared gray matter. Oligogenesis continued along lesion borders during the second week post-injury. Overall OL numbers were reduced at 3dpi in spared tissue, but rebounded to normal levels by 14dpi. Surprisingly, lesion borders maintained normal OL numbers at 3dpi, which then rose to exceed pre-injury levels at subsequently. These results indicate that oligogenesis after SCI leads to increased OL numbers and most new OLs are formed in regions of greatest NG2 cell proliferation. Thus, the adult spinal cord spontaneously develops a dynamic gliogenic zone along lesion borders. To elucidate mechanisms responsible for this post-traumatic oligodendrogenesis we chose examine ciliary neurotrophic factor (CNTF). Since CNTF, an astrocyte-derived growth factor, promotes OPC proliferation and differentiation into OLs and is upregulated in several CNS disorders, we hypothesized that CNTF expression is increased after SCI, especially in the regions of enhanced oligogenesis. Using a rat spinal contusion model, we quantified CNTF protein after SCI using Western blots. This revealed that CNTF expression continually rises between 5d and 28d post-injury (dpi). Using immunohistochemistry, we next determines CNTF distribution in tissue sections spanning the lesions at 3-28 dpi. CNTF was significantly increased in spared WM and GM at 5, 7, 14 and 28dpi compared to uninjured controls. At 7dpi, CNTF was equally high along lesion borders and outer spared tissue; by 28dpi CNTF was significantly elevated along lesion borders compared to spared tissue. Since CNTF can potentiate fibroblast growth factor-2 (FGF-2) expression which also promotes OPC proliferation; we quantified FGF-2+ve cells in the same regions as above. Indeed, significantly higher FGF-2+ve cells were noted along lesion borders and in spared GM suggesting that CNTF may promote FGF-2 expression in these regions. Since CNTF is upregulated in regions of prominent oligogenesis, CNTF may play a direct and/or indirect role in OL replacement after SCI. Collectively, these data elucidate a potential previously un-appreciated mechanism for CNS endogenous repair.
|Commitee:||Jakeman, Lyn, Lovett-Racke, Amy, Popovich, Phillip|
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Biomedical engineering, Pathology|
|Keywords:||CNTF, FGF, NG2, Oligodendrocyte, Progenitor, Spinal cord injury|
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