Hepatic stellate cells control liver zonation, size and functions via R-spondin 3
Hepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood<sup>1-5</sup>. 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.
Authors
- Guanxiong Wang
- Helen Remotti (ORCID: https://orcid.org/0000-0003-1555-9299)
- Atsushi Sugimoto (ORCID: https://orcid.org/0000-0003-3311-2562)
- Mojgan Masoodi (ORCID: https://orcid.org/0000-0001-9840-1731)
- Yujin Hoshida (ORCID: https://orcid.org/0000-0001-9430-1426)
- Presha Rajbhandari (ORCID: https://orcid.org/0000-0003-2184-7238)
- Utpal B. Pajvani (ORCID: https://orcid.org/0000-0001-5991-2723)
- Jonathan B. Steinman (ORCID: https://orcid.org/0000-0001-9492-4746)
- Hiroaki Kanzaki (ORCID: https://orcid.org/0000-0002-5039-9166)
- Brandon M. Lehrich (ORCID: https://orcid.org/0000-0003-1003-5605)
- Taruna V. Neelakantan
- Silvia Liu (ORCID: https://orcid.org/0000-0002-1840-9520)
- Naoto Fujiwara (ORCID: https://orcid.org/0000-0002-4109-3421)
- Yoshinobu Saito (ORCID: https://orcid.org/0000-0002-0624-0449)
- Brent R. Stockwell (ORCID: https://orcid.org/0000-0002-3532-3868)
- Samhita Ravi (ORCID: https://orcid.org/0000-0002-6731-734X)
- Hellmut G. Augustin (ORCID: https://orcid.org/0000-0002-7173-4242)
- Thomas Savage (ORCID: https://orcid.org/0000-0002-6618-2973)
- Michael Oertel (ORCID: https://orcid.org/0000-0002-2786-7013)
- Aveline A. Filliol (ORCID: https://orcid.org/0000-0002-1345-8147)
- Johannes C. Melms (ORCID: https://orcid.org/0000-0002-5410-6586)
- Satdarshan P. Monga (ORCID: https://orcid.org/0000-0002-8437-3378)
- Ki Hong Lee (ORCID: https://orcid.org/0009-0004-3640-4944)
- Chuan Yin (ORCID: https://orcid.org/0000-0002-5303-8278)
- Benjamin Izar (ORCID: https://orcid.org/0000-0003-2379-6702)
- Qiuyan Sun
- Adrien Guillot (ORCID: https://orcid.org/0000-0002-6002-9986)
- Marcella Steffani (ORCID: https://orcid.org/0000-0002-7439-7851)
- Mario Brosch (ORCID: https://orcid.org/0000-0001-8983-6557)
- Nicholas Arpaia (ORCID: https://orcid.org/0000-0002-0657-0528)
- Josepmaria Argemí (ORCID: https://orcid.org/0000-0003-1696-7753)
- Robert F. Schwabe (ORCID: https://orcid.org/0000-0003-4571-2098)
- Tyler M. Yasaka (ORCID: https://orcid.org/0000-0002-8482-0369)
- Rebecca A. Haeusler (ORCID: https://orcid.org/0000-0002-6973-9845)
- Yana Geng (ORCID: https://orcid.org/0000-0003-1529-0875)
- Jochen Hampe (ORCID: https://orcid.org/0000-0002-2421-6127)
- Timothy James Kendall (ORCID: https://orcid.org/0000-0002-4174-2786)
- Moritz Peiseler (ORCID: https://orcid.org/0000-0001-6195-3866)
- Frank Tacke (ORCID: https://orcid.org/0000-0001-6206-0226)
- Jonathan Andrew Fallowfield (ORCID: https://orcid.org/0000-0002-5741-1471)
- Youngmin A. Lee (ORCID: https://orcid.org/0000-0002-6567-7755)
- Storm Blockley-Powell (ORCID: https://orcid.org/0009-0009-8519-9904)
- Tian Lan
- Zhaoli Sun
- Deqi Yin (ORCID: https://orcid.org/0000-0002-0022-3269)
- Céline Hernandez (ORCID: https://orcid.org/0000-0002-8230-6016)
- Ramón Bataller (ORCID: https://orcid.org/0000-0002-1718-2985)
- Kevin C. Ray
- Jingran Qie
- Dhruv M. Goyal
Institutions
- Johns Hopkins University (US)
- University of Pittsburgh (US)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Columbia University Irving Medical Center (US)
- Johns Hopkins Medicine (US)
- University Hospital of Bern (CH)
- Instituto de Salud Carlos III (ES)
- University Hospital Heidelberg (DE)
- MRC Centre for Regenerative Medicine (GB)
- Center for Digestive and Liver Diseases (US)
- Human Longevity (United States) (US)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Clinica Universidad de Navarra (ES)
- University Medical Centre Mannheim (DE)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Herbert Irving Comprehensive Cancer Center
- Columbia University (US)
- Technische Universität Dresden (DE)
- Charité - Universitätsmedizin Berlin (DE)
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University Medical Center (US)
- The University of Osaka (JP)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature
- Published
- 2025-03-12
- DOI
- https://doi.org/10.1038/s41586-025-08677-w
- Citations
- 60
- Primary Topic
- Liver physiology and pathology
- Type
- article
- Field-Weighted Citation Impact
- 79.32