| In the 24 hours following contusive spinal cord injury (SCI), 50% of the oligodendrocytes and astrocytes of the epicenter are lost. By 6 weeks, however, the density of these cells returns to normal, suggesting that endogenous progenitors divide in response to injury. To investigate if cell proliferation is responsible for this recovery (chapter one), we injected rats with the thymidine analog bromo-deoxyuridine (BrdU), which is incorporated into the DNA of dividing cells during the synthesis (S) phase of mitosis. Quantification of dividing cells showed that proliferation of glial progenitors is significantly increased in the week after SCI, peaking on day 3. At 6 weeks, the progeny of these cells had differentiated into mature oligodendrocytes and astrocytes. Cell proliferation was greater in regions closer to the injury epicenter, suggesting its modulation by chemical factors that are released in response to injury. Three pro-mitotic growth factors that are upregulated after SCI were studied for a possible role in proliferation, using in situ hybridization and immunohistochemistry (chapter two). By comparing the expression pattern of each growth factor with the pattern of cell proliferation, glial growth factor 2 (GGF2) was chosen for further analysis of its involvement in post injury cell proliferation (chapter three). Administration of GGF2 increased cell proliferation in the week after SCI, and improved functional recovery by 4 weeks. At 6 weeks after SCI, GGF2 treated animals had greater oligodendrocyte and astrocyte density, and more spared white matter area. These studies show that cell proliferation plays a large role in repopulating the spinal cord after contusion injury. This mitotic reactivation is triggered by the injury-induced upregulation endogenous growth factors, and contributes to the spontaneous recovery observed after SCI. Exogenous administration of pro-mitotic growth factors further increases chronic cell density and functional recovery, providing a powerful tool for medical intervention following central nervous system trauma. |
