Sonic Hedgehog Pathway Activation Is Induced by Acute Brain Injury and Regulated by Injury-Related Inflammation
Sonic Hedgehog Pathway Activation Is Induced by Acute Brain Injury and Regulated by Injury-Related Inflammation
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DOI：
10.1523/jneurosci.2500-09.2009
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发表时间：
2009-08-19
影响因子：
5.3
通讯作者：
Holland, Eric C.
中科院分区：
文献类型：
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作者：
Amankulor, Nduka M.;Hambardzumyan, Dolores;Holland, Eric C.
成年哺乳动物脑通过激活细胞增殖程序对损伤作出反应，在此过程中，许多少突胶质细胞前体、小胶质细胞和一些星形胶质细胞增殖。脑损伤的另一种常见反应是诱导反应性神经胶质增生，这是一个休眠的星形胶质细胞发生形态变化并改变其转录谱的过程。虽然脑损伤诱导的反应性胶质增生与周围细胞的增殖是同时发生的，但反应性胶质增生与这种细胞增殖之间的功能关系尚未得到明确证明。在这里，我们表明，有丝分裂原音刺猬（SHH）是在大脑皮层损伤后的反应性星形胶质细胞中产生的，并参与调节脑损伤后表达Olig 2（+）细胞的增殖。使用皮质冷冻损伤诱导反应性胶质细胞增生的GLI-荧光素酶报告小鼠，我们表明，SHH通路是最活跃的脑损伤后3天，并返回到基线水平的14天。SHH表达与Gli激活平行，并定位于表达胶质细胞酸性蛋白的反应性星形胶质细胞。用环巴胺抑制SHH通路可以阻断Gli反应，并显著减少受损皮质中Olig 2（+）细胞的增殖和总数。为了提供星形胶质细胞中SHH通路激活的机制性见解，我们表明促炎刺激激活表达SHH的反应性星形胶质细胞，而通过巨噬细胞耗竭抑制炎症诱导的反应性神经胶质增生废除脑损伤后SHH激活并抑制损伤后细胞增殖。我们的数据描述了一个独特的反应性星形胶质细胞为基础，SHH表达的小生境形成的损伤和炎症，调节Olig 2（+）细胞的增殖。
The adult mammalian brain responds to injury by activating a program of cell proliferation during which many oligodendrocyte precursors, microglia, and some astrocytes proliferate. Another common response to brain injury is the induction of reactive gliosis, a process whereby dormant astrocytes undergo morphological changes and alter their transcriptional profiles. Although brain injury-induced reactive gliosis is concurrent with the proliferation of surrounding cells, a functional relationship between reactive gliosis and this cell proliferation has not been clearly demonstrated. Here, we show that the mitogen sonic hedgehog (SHH) is produced in reactive astrocytes after injury to the cerebral cortex and participates in regulating the proliferation of Olig2-expressing (Olig2(+)) cells after brain injury. Using a cortical freeze injury to induce reactive gliosis in a Gli-luciferase reporter mouse, we show that the SHH pathway is maximally active 3 d after brain injury and returns to baseline levels by 14 d. SHH expression parallels Gli activation and localizes to glial fibrillary acidic protein-expressing reactive astrocytes. Inhibition of the SHH pathway with cyclopamine blocks the Gli response and significantly reduces both the proliferating and overall number of Olig2(+) cells in the injured cortex. To provide mechanistic insight into SHH pathway activation in astrocytes, we show that proinflammatory stimuli activate SHH-expressing reactive astrocytes, whereas inhibition of inflammation-induced reactive gliosis by macrophage depletion abolishes SHH activation after brain injury and dampens cell proliferation after injury. Our data describes a unique reactive astrocyte-based, SHH-expressing niche formed in response to injury and inflammation that regulates the proliferation of Olig2(+) cells.