Endogenous GFAP-Positive Neural Stem/Progenitor Cells in the Postnatal Mouse Cortex Are Activated following Traumatic Brain Injury
Endogenous GFAP-Positive Neural Stem/Progenitor Cells in the Postnatal Mouse Cortex Are Activated following Traumatic Brain Injury
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DOI：
10.1089/neu.2011.1923
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发表时间：
2012-03-01
影响因子：
4.2
通讯作者：
Gray, William P.
中科院分区：
文献类型：
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作者：
Ahmed, Aminul I.;Shtaya, Anan B.;Gray, William P.
对促进受损神经系统再生的兴趣最近转向使用内源性干细胞。阐明在损伤后驱使这些前体细胞脱离静止状态的线索，以及驱使它们走向神经元和神经胶质谱系的信号，将有助于利用这些细胞进行修复。使用生物力学验证的体外器官型拉伸损伤模型，培养出生后小鼠的皮质-海马切片，并施加相当于严重创伤性脑损伤（TBI）的拉伸损伤。在未损伤的皮质中，在体外条件下，较老的切片几乎没有增殖潜力（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，这种潜能在受伤的外皮层恢复。通过对人类胶质纤维酸性蛋白（GFAP）启动子表达荧光报告基因的小鼠切片，我们发现GFAP +细胞占形成的增殖神经球的大多数，并且这些细胞可能来自皮质实质而不是脑室下区。此外，我们提供的证据表明，sonic hedgehog信号（一种已知的调节干细胞增殖的途径）的上调与TBI后再生潜力的恢复之间存在相关性。我们的研究结果表明，在体外创伤后，皮层和皮层下组织中存在一种静止的内源性干细胞。此外，这些增殖细胞是多能的，主要来源于表达gfap的细胞。这提高了使用这种内源性干细胞进行TBI后修复的可能性。
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.