Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Neurochem Int. 2024 Nov;180:105862. doi: 10.1016/j.neuint.2024.105862. Epub 2024 Sep 20.
Fibrotic scar formation is a critical pathological change impacting tissue reconstruction and functional recovery after ischemic stroke. The regulatory mechanisms behind fibrotic scarring in the central nervous system (CNS) remain largely unknown. While macrophages are known to play a role in fibrotic scar formation in peripheral tissues, the involvement of microglia, the resident immune cells of the CNS, in CNS fibrosis requires further exploration. The Sonic Hedgehog (Shh) signaling pathway, pivotal in embryonic development and tissue regeneration, is also crucial in modulating fibrosis in peripheral tissues. However, the impact and regulatory mechanisms of Shh on fibrotic scar formation post-ischemic stroke have not been thoroughly investigated.
This study explores whether Shh can regulate fibrotic scar formation post-ischemic stroke and its underlying mechanisms through in vivo and in vitro manipulation of Shh expression.
Our results showed that Shh expression was upregulated in the serum of acute ischemic stroke patients, as well as in the serum, CSF, and ischemic regions of MCAO/R mice. Moreover, the upregulation of Shh expression was positively correlated with fibrotic scar formation and M2 microglial polarization. Shh knockdown inhibited fibrotic scar formation and M2 microglial polarization while aggravating neurological deficits in MCAO/R mice. In vitro, adenoviral knockdown or Smoothened Agonist (SAG) activation of Shh expression in BV2 cells following OGD/R regulated their polarization and influenced the expression of TGFβ1 and PDGFA, subsequently affecting fibroblast activation.
These results suggest that Shh regulates M2 microglial polarization and fibrotic scar formation after cerebral ischemia.
纤维化瘢痕形成是影响缺血性脑卒中后组织重建和功能恢复的关键病理变化。中枢神经系统（CNS）纤维化瘢痕形成的调控机制在很大程度上尚不清楚。虽然巨噬细胞在周围组织的纤维化瘢痕形成中起作用，但中枢神经系统固有免疫细胞小胶质细胞在 CNS 纤维化中的参与仍需要进一步探索。Sonic Hedgehog（Shh）信号通路在胚胎发育和组织再生中起关键作用，在调节周围组织纤维化中也至关重要。然而，Shh 对缺血性脑卒中后纤维化瘢痕形成的影响及其调控机制尚未得到深入研究。
本研究通过体内和体外操纵 Shh 表达，探讨 Shh 是否可以调节缺血性脑卒中后纤维化瘢痕形成及其潜在机制。
我们的结果表明，Shh 表达在急性缺血性脑卒中患者的血清中以及 MCAO/R 小鼠的血清、CSF 和缺血区域中上调。此外，Shh 表达的上调与纤维化瘢痕形成和 M2 小胶质细胞极化呈正相关。Shh 敲低抑制 MCAO/R 小鼠的纤维化瘢痕形成和 M2 小胶质细胞极化，同时加重神经功能缺损。在体外，BV2 细胞在 OGD/R 后通过腺病毒敲低或 Smoothened 激动剂（SAG）激活 Shh 表达，调节其极化，并影响 TGFβ1 和 PDGFA 的表达，进而影响成纤维细胞的激活。
这些结果表明，Shh 调节脑缺血后 M2 小胶质细胞极化和纤维化瘢痕形成。
