Fibrotic scar formation after cerebral ischemic stroke:Targeting the Sonic hedgehog signaling pathway for scar reduction  

作　　者：un Wen Hao Tang Mingfen Tian Ling Wang Qinghuan Yang Yong Zhao Xuemei Li Yu Ren Jiani Wang Li Zhou Yongjun Tan Haiyun Wu Xinrui Cai Yilin Wang Hui Cao Jianfeng Xu Qin Yang 

机构地区：[1]Department of Neurology,The Frist Affiliated Hospital of Chongqing Medical University,Chongqing,China [2]Department of Neurology,Second People’s Hospital of Chongqing Banan District,Chongqing,China [3]Department of Neurosurgery,Third Hospital of Mianyang,Mianyang,Sichuan Province,China

出　　处：《Neural Regeneration Research》2026年第2期756-768,共13页中国神经再生研究(英文版)

基　　金：supported by the National Natural Science Foundation of China,Nos.82171456(to QY)and 81971229(to QY);the Natural Science Foundation of Chongqing,Nos.CSTC2021JCYJ-MSXMX0263(to QY)and CSTB2023NSCQ-MSX1015(to XL);Doctoral Innovation Project of The First Affiliated Hospital of Chongqing Medical University,Nos.CYYY-BSYJSCXXM-202318(to JW)and CYYY-BSYJSCXXM-202327(to HT).

摘　　要：Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.

关 键 词：central nervous system FIBROBLASTS fibrosis ischemic stroke Mitofusin 2 middle cerebral artery occlusion/reperfusion P-Smad3 Sonic Hedgehog SMAD3 TOM20 

分 类 号：R743.3[医药卫生—神经病学与精神病学]