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

Atsushi Sugimoto, Yoshinobu Saito, Guanxiong Wang, Qiuyan Sun, Chuan Yin, Ki Hong Lee, Yana Geng, Presha Rajbhandari, Celine Hernandez, Marcella Steffani, Jingran Qie, Thomas Savage, Dhruv M. Goyal, Kevin C. Ray, Taruna V. Neelakantan, Deqi Yin, Johannes Melms, Brandon M. Lehrich, Tyler M. Yasaka, Silvia Liu, Michael Oertel, Tian Lan, Adrien Guillot, Moritz Peiseler, Aveline Filliol, Hiroaki Kanzaki, Naoto Fujiwara, Samhita Ravi, Benjamin Izar, Mario Brosch, Jochen Hampe, Helen Remotti, Josepmaria Argemi, Zhaoli Sun, Timothy J. Kendall, Yujin Hoshida, Frank Tacke, Jonathan A. Fallowfield, Storm K. Blockley-Powell, Rebecca A. Haeusler, Jonathan B. Steinman, Utpal B. Pajvani, Satdarshan P. Monga, Ramon Bataller, Mojgan Masoodi, Nicholas Arpaia, Youngmin A. Lee, Brent R. Stockwell, Hellmut G. Augustin () and Robert F. Schwabe ()
Additional contact information
Atsushi Sugimoto: Columbia University
Yoshinobu Saito: Columbia University
Guanxiong Wang: German Cancer Research Center
Qiuyan Sun: Columbia University
Chuan Yin: Columbia University
Ki Hong Lee: German Cancer Research Center
Yana Geng: Columbia University
Presha Rajbhandari: Columbia University
Celine Hernandez: Columbia University
Marcella Steffani: Columbia University
Jingran Qie: Columbia University
Thomas Savage: Columbia University
Dhruv M. Goyal: Columbia University
Kevin C. Ray: Vanderbilt University Medical Center
Taruna V. Neelakantan: Columbia University
Deqi Yin: Columbia University
Johannes Melms: Columbia University
Brandon M. Lehrich: University of Pittsburgh School of Medicine
Tyler M. Yasaka: University of Pittsburgh School of Medicine
Silvia Liu: University of Pittsburgh School of Medicine
Michael Oertel: University of Pittsburgh School of Medicine
Tian Lan: Charité—Universitätsmedizin Berlin
Adrien Guillot: Charité—Universitätsmedizin Berlin
Moritz Peiseler: Charité—Universitätsmedizin Berlin
Aveline Filliol: Columbia University
Hiroaki Kanzaki: University of Texas Southwestern Medical Center
Naoto Fujiwara: University of Texas Southwestern Medical Center
Samhita Ravi: University of Pittsburgh School of Medicine
Benjamin Izar: Columbia University
Mario Brosch: Technische Universität Dresden
Jochen Hampe: Technische Universität Dresden
Helen Remotti: Columbia University Digestive and Liver Disease Research Center
Josepmaria Argemi: Cancer Center Clínica Universidad de Navarra (CCUN)
Zhaoli Sun: Johns Hopkins University School of Medicine
Timothy J. Kendall: University of Edinburgh
Yujin Hoshida: University of Texas Southwestern Medical Center
Frank Tacke: Charité—Universitätsmedizin Berlin
Jonathan A. Fallowfield: University of Edinburgh
Storm K. Blockley-Powell: Columbia University
Rebecca A. Haeusler: Columbia University
Jonathan B. Steinman: Columbia University
Utpal B. Pajvani: Columbia University
Satdarshan P. Monga: University of Pittsburgh School of Medicine
Ramon Bataller: Hospital Clinic
Mojgan Masoodi: Bern University Hospital
Nicholas Arpaia: Columbia University Digestive and Liver Disease Research Center
Youngmin A. Lee: Vanderbilt University Medical Center
Brent R. Stockwell: Columbia University Digestive and Liver Disease Research Center
Hellmut G. Augustin: German Cancer Research Center
Robert F. Schwabe: Columbia University

Nature, 2025, vol. 640, issue 8059, 752-761

Abstract: Abstract Hepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood1–5. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08677-w

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