Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis.
Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis.
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靶向YAP介导的HSC死亡易感性和衰老治疗肝纤维化。
DOI：
10.1097/hep.0000000000000326
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发表时间：
2023-06-01
期刊：
影响因子：
13.5
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Du, Kuo;Maeso-Diaz, Raquel;Oh, Seh Hoon;Wang, Ergang;Chen, Tianyi;Pan, Christopher;Xiang, Kun;Dutta, Rajesh Kumar;Wang, Xiao-Fan;Chi, Jen-Tsan;Diehl, Anna Mae
肝纤维化是由来源于静止肝星状细胞（HSC）的肌成纤维细胞（MF）积累引起的，并且雅普（yes相关蛋白）控制这种状态转变。虽然纤维化也受到HSC死亡和衰老的影响，但雅普是否调节这些过程以及这是否可以用于治疗肝纤维化尚不清楚。在MF-HSC中操纵雅普活性以确定雅普如何影响对促凋亡衰老清除剂或铁凋亡的易感性。衰老对雅普活性的影响和对细胞凋亡与铁凋亡的敏感性也进行了研究。用铁凋亡诱导剂或促凋亡衰老清除剂处理CCl 4处理的小鼠，以确定对肝纤维化的影响。在MF中有条件地破坏雅普以确定MF-HSC中的雅普活性如何影响小鼠模型中的肝纤维化。在培养的MF-HSC中沉默雅普诱导HSC衰老和对衰老抑制剂的脆弱性，并促进铁凋亡抗性。相反，诱导HSC衰老抑制了雅普活性，增加了对衰老抑制剂的敏感性，并降低了对铁凋亡的敏感性。肝纤维化的HSC的单细胞分析揭示了对铁凋亡、凋亡和衰老的异质敏感性。在慢性肝损伤的小鼠中，无论是铁凋亡诱导剂还是衰老清除剂都不能改善纤维化。然而，选择性消耗MF-HSC中的雅普诱导衰老并减少肝损伤和纤维化。雅普决定MF-HSC是否保持活化或变得衰老。通过调节这种状态转换，雅普控制HSC纤维化活性和对细胞死亡不同机制的敏感性。MF-HSC特异性的雅普蛋白缺失可诱导衰老并保护受损肝脏免受纤维化。阐明HSC雅普活性的决定因素可能有助于开发新的抗纤维化疗法。
Liver fibrosis results from accumulation of myofibroblasts (MFs) derived from quiescent hepatic stellate cells (HSCs), and YAP (yes-associated protein) controls this state transition. Although fibrosis is also influenced by HSC death and senescence, whether YAP regulates these processes and this could be leveraged to treat liver fibrosis are unknown. YAP activity was manipulated in MF-HSCs to determine how YAP impacts susceptibility to pro-apoptotic senolytic agents or ferroptosis. Effects of senescence on YAP activity and susceptibility to apoptosis versus ferroptosis were also examined. CCl4-treated mice were treated with a ferroptosis inducer or pro-apoptotic senolytic to determine effects on liver fibrosis. YAP was conditionally disrupted in MFs to determine how YAP activity in MF-HSC affects liver fibrosis in mouse models. Silencing YAP in cultured MF-HSCs induced HSC senescence and vulnerability to senolytics, and promoted ferroptosis resistance. Conversely, inducing HSC senescence suppressed YAP activity, increased sensitivity to senolytics, and decreased sensitivity to ferroptosis. Single cell analysis of HSCs from fibrotic livers revealed heterogeneous sensitivity to ferroptosis, apoptosis, and senescence. In mice with chronic liver injury, neither the ferroptosis inducer nor senolytic improved fibrosis. However, selectively depleting YAP in MF-HSCs induced senescence and decreased liver injury and fibrosis. YAP determines whether MF-HSCs remain activated or become senescent. By regulating this state transition, Yap controls both HSC fibrogenic activity and susceptibility to distinct mechanisms for cell death. MF-HSC-specific YAP depletion induces senescence and protects injured livers from fibrosis. Clarifying determinants of HSC YAP activity may facilitate development of novel anti-fibrotic therapies.