Oligodendrogenesis following experimental spinal cord injury

Trauma to the spinal cord causes oligodendrocyte (OL) cell death and axonal demyelination. Spontaneous recovery following spinal cord injury (SCI) is quite limited due to severe axonal damage and very poor axonal regeneration. The mature central nervous system (CNS) contains oligodendrocyte progenitor cells (OPCs) which make the replacement of lost OLs possible. Our goals were fourfold: study SCI induced changes in endogenous OPCs in different regions of the spinal cord over time; evaluate the inherent capability of the injured cord to generate new OLs; determine if any noted oligogenesis affects OL population dynamics and finally determine which endogenous factors contributing to OPC proliferation and differentiation.; We were interested in overall expression patterns of NG2 after SCI. Following SCI no changes in the overall NG2 protein expression were seen at the epicenter 3 days post injury (dpi) but between 7-70dpi, NG2 expression increased significantly to occupy almost 50% of the cross-sectional area. Even 4mm distal to the injury site, NG2 immunoreactivity was still elevated 2-fold over naive between 7-70dpi. Although NG2 expression increased in all of the tissue, early upregulation of NG2 was especially prominent along the lesion border.; To determine if the proliferating OPCs gave rise to new OLs, we examined whether new OLs (BrdU+) were present in regions of high NG2 cell proliferation. Mature OLs are post-mitotic and cannot re-enter the cell cycle hence a BrdU+ OL must have differentiated from a cycling progenitor. At all days examined during the first 2 weeks post injury, significantly higher oligodendrogenesis occurred in all regions examined compared to naive, with the greatest increases occurring in the gray matter and in regions around the lesion border. The enhanced oligogenesis normalized OL numbers in the spared white matter by 7dpi, and along the lesion border at 7d and 14dpi OL numbers were more than 2-fold greater than in normal WM.; We hypothesized that astrocyte derived growth factors contribute to enhanced oligodendrogenesis in the perilesion area. We chose to examine ciliary neurotrophic factor (CNTF) since it promotes the rate of OPC proliferation and maturation as well as enhances OL survival. Following SCI astrocytes were the major source of CNTF, although we also noted CNTF immunoreactivity on OLs and Schwann cells. From this it was clear that CNTF immunoreactivity was present throughout the injured tissue, with most immunoreactivity localized to lesion borders, which, as stated above, were the regions showing the greatest level of oligodendrogenesis.; Another potential factor that may contribute to oligogenesis after SCI is fibroblast growth factor-2 (FGF-2). FGF-2 promotes NG2 cell proliferation and migration and studies have shown that CNTF enhances FGF-2 mediated effects. Therefore, we also examined FGF-2 expression at 7dpi after SCI. Significantly higher numbers of FGF-2 expressing cells were present in the WM bordering the lesion compared to the SWM.; Hence collectively, our work shows that subsequent to marked NG2 cell proliferation, there is a previously unrecognized robust oligogenic response during the first 2 weeks following SCI. This oligogenesis was particularly prominent along the lesion border and resulted in replacement and normalization of OL numbers in spared tissue. This marked increase in OLs may be due, at least in part, to SCI-induced up regulation of CNTF and FGF-2. Thus the mature CNS has a remarkable self-reparative potential. Our understanding of in-vivo mechanisms underlying this significant oligogenesis in such severe conditions will further our strategies aimed at better outcomes following cell transplantation or enhancing the endogenous repair mechanisms not only following SCI but additional disorders targeting OL loss. (Abstract shortened by UMI.)...