Departments of Biology and Neurobiology and Anatomy, Drexel University, Philadelphia, PA, 19104, USA.
Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Sci Rep. 2019 Jan 24;9(1):565. doi: 10.1038/s41598-018-37555-x.
Following injury to the central nervous system, astrocytes perform critical and complex functions that both promote and antagonize neural repair. Understanding the molecular signaling pathways that coordinate their diverse functional properties is key to developing effective therapeutic strategies. In the healthy, adult CNS, Sonic hedgehog (Shh) signaling is active in mature, differentiated astrocytes. Shh has been shown to undergo injury-induced upregulation and promote neural repair. Here, we investigated whether Shh signaling mediates astrocyte response to injury. Surprisingly, we found that following an acute, focal injury, reactive astrocytes exhibit a pronounced reduction in Shh activity in a spatiotemporally-defined manner. Shh signaling is lost in reactive astrocytes at the lesion site, but persists in mild to moderately reactive astrocytes in distal tissues. Nevertheless, local pharmacological activation of the Shh pathway in astrocytes mitigates inflammation, consistent with a neuroprotective role for Shh signaling after injury. Interestingly, we find that Shh signaling is restored to baseline levels two weeks after injury, a time during which acute inflammation has largely subsided and lesions have matured. Taken together, these data suggest that endogenous Shh signaling in astrocytes is dynamically regulated in a context dependent manner. In addition, exogenous activation of the Shh pathway promotes neuroprotection mediated by reactive astrocytes.
中枢神经系统损伤后，星形胶质细胞发挥着关键而复杂的作用，既能促进也能拮抗神经修复。了解协调其多种功能特性的分子信号通路是开发有效治疗策略的关键。在健康的成年中枢神经系统中，Sonic hedgehog（Shh）信号在成熟分化的星形胶质细胞中活跃。已经表明 Shh 会在损伤诱导下上调并促进神经修复。在这里，我们研究了 Shh 信号是否介导星形胶质细胞对损伤的反应。令人惊讶的是，我们发现，在急性局灶性损伤后，反应性星形胶质细胞以时空限定的方式表现出 Shh 活性的明显降低。Shh 信号在损伤部位的反应性星形胶质细胞中丢失，但在远端组织中轻度至中度反应性星形胶质细胞中持续存在。然而，局部药理学激活星形胶质细胞中的 Shh 途径可减轻炎症，这与损伤后 Shh 信号的神经保护作用一致。有趣的是，我们发现 Shh 信号在损伤后两周恢复到基线水平，此时急性炎症已基本消退，病变已成熟。总之，这些数据表明星形胶质细胞中的内源性 Shh 信号以依赖于上下文的方式动态调节。此外，Shh 途径的外源性激活促进了反应性星形胶质细胞介导的神经保护作用。
