Hepatic stellate cells control liver zonation, size and functions via R-spondin 3

• 成果类型: Article
• 署名作者: Sugimoto, Atsushi; Saito, Yoshinobu; Wang, Guanxiong; Sun, Qiuyan; Yin, Chuan; Lee, Ki Hong; Geng, Yana; Rajbhandari, Presha; Hernandez, Celine; Steffani, Marcella; Qie, Jingran; Savage, Thomas; Goyal, Dhruv M.; Ray, Kevin C.; Neelakantan, Taruna V.; Yin, Deqi; Melms, Johannes; Lehrich, Brandon M.; Yasaka, Tyler M.; Liu, Silvia; Oertel, Michael; Lan, Tian; Guillot, Adrien; Peiseler, Moritz; Filliol, Aveline; Kanzaki, Hiroaki; Fujiwara, Naoto; Ravi, Samhita; Izar, Benjamin; Brosch, Mario; Hampe, Jochen; Remotti, Helen; Argemi, Josepmaria; Sun, Zhaoli; Kendall, Timothy J.; Hoshida, Yujin; Tacke, Frank; Fallowfield, Jonathan A.; Blockley-Powell, Storm K.; Haeusler, Rebecca A.; Steinman, Jonathan B.; Pajvani, Utpal B.; Monga, Satdarshan P.; Bataller, Ramon; Masoodi, Mojgan; Arpaia, Nicholas; Lee, Youngmin A.; Stockwell, Brent R.; Augustin, Hellmut G.; Schwabe, Robert F.
• 署名单位: Columbia University; Columbia University; University of Osaka; Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; Columbia University; Columbia University; Columbia University; Vanderbilt University; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; University of Texas System; University of Texas Southwestern Medical Center; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Columbia University; Technische Universitat Dresden; Carl Gustav Carus University Hospital; Technische Universitat Dresden; NewYork-Presbyterian Hospital; Columbia University; University of Navarra; University of Navarra; Instituto de Salud Carlos III; CIBER - Centro de Investigacion Biomedica en Red; CIBEREHD; Johns Hopkins University; University of Edinburgh; Columbia University; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; University of Bern; University Hospital of Bern; Columbia University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3220
• DOI: 10.1038/s41586-025-08677-w
• 发表日期: 2025-04-17
• 关键词: catenin knockout mice; beta-catenin; hepatocellular-carcinoma; GROWTH; expression; regeneration; homeostasis; metabolism; promotion; depletion

摘要

Hepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood1, 2, 3, 4-5. Here we demonstrate that genetic depletion of HSCs changes WNT activity and zonation of hepatocytes, leading to marked alterations in liver regeneration, cytochrome P450 metabolism and injury. We identify R-spondin 3 (RSPO3), an HSC-enriched modulator of WNT signalling, as responsible for these hepatocyte-regulatory effects of HSCs. HSC-selective deletion of Rspo3 phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, liver size, regeneration and cytochrome P450-mediated detoxification, and exacerbates alcohol-associated and metabolic dysfunction-associated steatotic liver disease. RSPO3 expression decreases with HSC activation and is inversely associated with outcomes in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These protective and hepatocyte-regulating functions of HSCs via RSPO3 resemble the R-spondin-expressing stromal niche in other organs and should be integrated into current therapeutic concepts.