Zhang Yinliang, Gai Xiaochen, Li Yuhui, Chen Zuoyu, Zhang Xi, Qiao Wei, Qiu Ping, Du Chunyuan, Sheng Sufang, Hao Jingran, Zhang Yujie, Fan Heng, Li Xiaorong, Liu Ming, Zhang Jun, Pan Zhe, Chang Yongsheng
Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
School of Life Sciences, Westlake University, Hangzhou, 310000, China.
Adv Sci (Weinh). 2025 May;12(19):e2500616. doi: 10.1002/advs.202500616. Epub 2025 Mar 24.
Hepatic stellate cells (HSCs) play a central role in the development of liver fibrosis, and their activation is controlled by a complex interplay of autocrine/paracrine signals within the liver microenvironment. Here, we show that growth differentiation factor 10 (GDF10) is specifically expressed by HSCs in both mouse and human livers, and its expression is reduced in activated HSCs. Loss of GDF10 function promotes HSC activation and exacerbates liver fibrosis in mice, while gain of GDF10 function alleviates this pathological condition. Mechanistically, autocrine GDF10 binds to BMPR2/ALK3 receptor to elicit SMAD1/5/8-SMAD7 signaling pathway in HSCs. Activated SMAD1/5/8-SMAD7 signaling pathway then inhibits the TGF-β-SMAD2/3 signaling transduction, which is essential for HSC activation. Moreover, recombinant GDF10 protein treatment suppresses HSC activation and alleviates liver fibrosis in mice. In conclusion, GDF10 is an autocrine suppressor of HSC activation and a potential therapeutic target for the treatment of liver fibrosis.
肝星状细胞（HSCs）在肝纤维化的发展中起核心作用，其激活受肝微环境中自分泌/旁分泌信号复杂相互作用的控制。在此，我们表明生长分化因子10（GDF10）在小鼠和人类肝脏中均由肝星状细胞特异性表达，且其在活化的肝星状细胞中的表达降低。GDF10功能缺失促进小鼠肝星状细胞激活并加剧肝纤维化，而GDF10功能获得则减轻这种病理状况。机制上，自分泌的GDF10与BMPR2/ALK3受体结合，在肝星状细胞中引发SMAD1/5/8 - SMAD7信号通路。激活的SMAD1/5/8 - SMAD7信号通路随后抑制对肝星状细胞激活至关重要的TGF-β - SMAD2/3信号转导。此外，重组GDF10蛋白治疗可抑制小鼠肝星状细胞激活并减轻肝纤维化。总之，GDF10是肝星状细胞激活的自分泌抑制因子，也是治疗肝纤维化的潜在治疗靶点。
