Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, UK.
J Neurotrauma. 2012 Mar 20;29(5):828-42. doi: 10.1089/neu.2011.1923. Epub 2011 Dec 14.
Interest in promoting regeneration of the injured nervous system has recently turned toward the use of endogenous stem cells. Elucidating cues involved in driving these precursor cells out of quiescence following injury, and the signals that drive them toward neuronal and glial lineages, will help to harness these cells for repair. Using a biomechanically validated in vitro organotypic stretch injury model, cortico-hippocampal slices from postnatal mice were cultured and a stretch injury equivalent to a severe traumatic brain injury (TBI) applied. In uninjured cortex, proliferative potential under in vitro conditions is virtually absent in older slices (equivalent postnatal day 15 compared to 8). However, following a severe stretch injury, this potential is restored in injured outer cortex. Using slices from mice expressing a fluorescent reporter on the human glial fibrillary acidic protein (GFAP) promoter, we show that GFAP+ cells account for the majority of proliferating neurospheres formed, and that these cells are likely to arise from the cortical parenchyma and not from the subventricular zone. Moreover, we provide evidence for a correlation between upregulation of sonic hedgehog signaling, a pathway known to regulate stem cell proliferation, and this restoration of regenerative potential following TBI. Our results indicate that a source of quiescent endogenous stem cells residing in the cortex and subcortical tissue proliferate in vitro following TBI. Moreover, these proliferating cells are multipotent and are derived mostly from GFAP-expressing cells. This raises the possibility of using this endogenous source of stem cells for repair following TBI.
人们对促进受损神经系统再生的兴趣最近转向了内源性干细胞的应用。阐明损伤后驱使这些前体细胞从静止状态中活跃起来的线索，以及驱使它们向神经元和神经胶质谱系分化的信号，将有助于利用这些细胞进行修复。本研究使用一种经生物力学验证的体外器官型拉伸损伤模型，培养来自新生小鼠的皮质 - 海马切片，并施加相当于严重创伤性脑损伤 (TBI) 的拉伸损伤。在未受伤的皮质中，在体外条件下，增殖潜能在较老的切片中几乎不存在（相当于出生后第 15 天，而不是第 8 天）。然而，在严重的拉伸损伤后，这种潜能在外层皮质的损伤部位得到了恢复。使用表达人胶质纤维酸性蛋白 (GFAP) 启动子荧光报告基因的小鼠切片，我们表明，GFAP+细胞构成了大多数形成的增殖神经球的主要成分，并且这些细胞可能来自皮质实质，而不是侧脑室下区。此外，我们提供的证据表明，声波刺猬信号通路的上调与 TBI 后再生潜能的恢复之间存在相关性，该通路已知可调节干细胞增殖。我们的研究结果表明，在 TBI 后，静息的内源性干细胞源位于皮质和皮质下组织中，并在体外增殖。此外，这些增殖细胞具有多能性，主要来源于表达 GFAP 的细胞。这就提出了利用这种内源性干细胞源在 TBI 后进行修复的可能性。
