He Jianbo, Li Shuang, Yang Zhuolin, Ma Jianlong, Qian Chuanfang, Huang Zhuofu, Li Linke, Yang Yun, Chen Jingying, Sun Yunfan, Zhao Tianyu, Luo Lingfei
State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China.
Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China.
Nat Cell Biol. 2025 Jan;27(1):39-47. doi: 10.1038/s41556-024-01568-8. Epub 2025 Jan 8.
Severe damage to the intrahepatic biliary duct (IHBD) network occurs in multiple human advanced cholangiopathies, such as primary sclerosing cholangitis, biliary atresia and end-stage primary biliary cholangitis. Whether and how a severely damaged IHBD network could reconstruct has remained unclear. Here we show that, although the gallbladder is not directly connected to the IHBD, there is a common hepatic duct (CHD) in between, and severe damage to the IHBD network induces migration of gallbladder smooth muscle cells (SMCs) to coat the CHD in mouse and zebrafish models. These gallbladder-derived, CHD-coating SMCs produce retinoic acid to activate Sox9b in the CHD, which drives proliferation and ingrowth of CHD cells into the inner liver to reconstruct the IHBD network. This study reveals a hitherto unappreciated function of the gallbladder in the recovery of injured liver, and characterizes mechanisms involved in how the gallbladder and liver communicate through inter-organ cell migration to drive tissue regeneration. Carrying out cholecystectomy will thus cause previously unexpected impairments to liver health.
肝内胆管（IHBD）网络的严重损伤发生在多种人类晚期胆管疾病中，如原发性硬化性胆管炎、胆道闭锁和终末期原发性胆汁性胆管炎。严重受损的IHBD网络是否以及如何重建仍不清楚。在这里，我们表明，尽管胆囊与IHBD没有直接连接，中间有一条肝总管（CHD），但在小鼠和斑马鱼模型中，IHBD网络的严重损伤会诱导胆囊平滑肌细胞（SMC）迁移以覆盖CHD。这些源自胆囊的、覆盖CHD的SMC产生视黄酸以激活CHD中的Sox9b，从而驱动CHD细胞增殖并向内生长到肝脏内部以重建IHBD网络。这项研究揭示了胆囊在受损肝脏恢复中迄今未被认识到的功能，并描述了胆囊和肝脏如何通过器官间细胞迁移进行通信以驱动组织再生的机制。因此，进行胆囊切除术将对肝脏健康造成先前意想不到的损害。
