Zai Laila J, Yoo Soonmoon, Wrathall Jean R
Department of Neuroscience, Georgetown University, NRB-EG31, Washington, DC 20057, USA.
Brain Res. 2005 Aug 9;1052(2):147-55. doi: 10.1016/j.brainres.2005.05.071.
The damage caused by traumatic central nervous system (CNS) injury can be divided into two phases: primary and secondary. The initial injury destroys many of the local neurons and glia and triggers secondary mechanisms that result in further cell loss. Approximately 50% of the astrocytes and oligodendrocytes in the spared white matter of the epicenter die by 24 h after spinal cord injury (SCI), but their densities return to normal levels by 6 weeks. This repopulation is largely due to the proliferation of local progenitors that divide in response of CNS injury. Previous studies indicate that the secondary events that cause cell death after SCI also increase the local levels of several growth factors that stimulate the proliferation of these endogenous progenitors. We compared the spatial pattern of the post-injury up-regulation of the pro-mitotic growth factors with that of 5-bromodeoxyuridine (BrdU) incorporation to determine if each could play a role in proliferation. Three days after a standard contusive SCI or laminectomy, animals received intraperitoneal BrdU injections to label dividing cells and were perfused 2 h after the last injection. Immunohistochemistry for BrdU and basic fibroblast growth factor (FGF2) and in situ hybridization for ciliary neurotrophic factor (CNTF) and glial growth factor (GGF2) mRNA were used to compare the number of dividing cells with growth factor levels in sections 2 and 4 mm from the epicenter. All three growth factors are significantly up-regulated 3 days after SCI, when cell proliferation is maximal. The increase in GGF2 and FGF2 levels is highest in sections 2 mm rostral to the epicenter, mimicking BrdU incorporation. Addition of rhGGF2 to cultured cells isolated from the spinal cord 3 days after SCI increased the number of NG2+ glial progenitors. These data suggest that FGF2 and GGF2 may contribute to the spontaneous recovery observed after SCI by stimulating the proliferation of local progenitors that help repopulate the injured cord.
创伤性中枢神经系统（CNS）损伤所造成的损害可分为两个阶段：原发性和继发性。初始损伤会破坏许多局部神经元和神经胶质细胞，并触发导致进一步细胞丢失的继发性机制。脊髓损伤（SCI）后24小时内，震中未受损白质中约50%的星形胶质细胞和少突胶质细胞死亡，但到6周时其密度恢复到正常水平。这种细胞重新填充主要是由于局部祖细胞的增殖，这些祖细胞会响应中枢神经系统损伤而分裂。先前的研究表明，SCI后导致细胞死亡的继发性事件也会增加几种生长因子的局部水平，这些生长因子会刺激这些内源性祖细胞的增殖。我们比较了促有丝分裂生长因子损伤后上调的空间模式与5-溴脱氧尿苷（BrdU）掺入的空间模式，以确定它们是否都能在增殖中发挥作用。在标准挫伤性SCI或椎板切除术后三天，给动物腹腔注射BrdU以标记分裂细胞，并在最后一次注射后2小时进行灌注。使用针对BrdU和碱性成纤维细胞生长因子（FGF2）的免疫组织化学以及针对睫状神经营养因子（CNTF）和神经胶质生长因子（GGF2）mRNA的原位杂交，来比较震中2毫米和4毫米处切片中分裂细胞的数量与生长因子水平。所有三种生长因子在SCI后三天均显著上调，此时细胞增殖最为旺盛。GGF2和FGF2水平的增加在震中前方2毫米处的切片中最高，与BrdU掺入情况相似。在SCI后三天向从脊髓分离的培养细胞中添加重组人GGF2（rhGGF2），增加了NG2 +神经胶质祖细胞的数量。这些数据表明，FGF2和GGF2可能通过刺激局部祖细胞的增殖来促进SCI后观察到的自发恢复，这些局部祖细胞有助于重新填充受损脊髓。
