Cover Image

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 understood1-5. Here we demonstrate that genetic depletion of HSCs changes WNT activity and zonation of hepatocytes, leading...

Full description

Saved in:
Bibliographic Details
Main Authors: Sugimoto, Atsushi (Author) , Saito, Yoshinobu (Author) , Wang, Guanxiong (Author) , Sun, Qiuyan (Author) , Yin, Chuan (Author) , Lee, Ki Hong (Author) , Geng, Yana (Author) , Rajbhandari, Presha (Author) , Hernandez, Celine (Author) , Steffani, Marcella (Author) , Qie, Jingran (Author) , Savage, Thomas (Author) , Goyal, Dhruv M. (Author) , Ray, Kevin C. (Author) , Neelakantan, Taruna V. (Author) , Yin, Deqi (Author) , Melms, Johannes (Author) , Lehrich, Brandon M. (Author) , Yasaka, Tyler M. (Author) , Liu, Silvia (Author) , Oertel, Michael (Author) , Lan, Tian (Author) , Guillot, Adrien (Author) , Peiseler, Moritz (Author) , Filliol, Aveline (Author) , Kanzaki, Hiroaki (Author) , Fujiwara, Naoto (Author) , Ravi, Samhita (Author) , Izar, Benjamin (Author) , Brosch, Mario (Author) , Hampe, Jochen (Author) , Remotti, Helen (Author) , Argemi, Josepmaria (Author) , Sun, Zhaoli (Author) , Kendall, Timothy J. (Author) , Hoshida, Yujin (Author) , Tacke, Frank (Author) , Fallowfield, Jonathan A. (Author) , Blockley-Powell, Storm K. (Author) , Haeusler, Rebecca A. (Author) , Steinman, Jonathan B. (Author) , Pajvani, Utpal B. (Author) , Monga, Satdarshan P. (Author) , Bataller, Ramon (Author) , Masoodi, Mojgan (Author) , Arpaia, Nicholas (Author) , Lee, Youngmin A. (Author) , Stockwell, Brent R. (Author) , Augustin, Hellmut (Author) , Schwabe, Robert F. (Author)
Format: Article (Journal)
Language:English
Published: 17 April 2025
In: Nature
Year: 2025, Volume: 640, Issue: 8059, Pages: 752-761
ISSN:1476-4687
DOI:10.1038/s41586-025-08677-w
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41586-025-08677-w
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41586-025-08677-w
Get full text
Author Notes: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 & Robert F. Schwabe
Description
Summary: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.
Item Description:Online veröffentlicht: 12. März 2025
Gesehen am 18.06.2025
Physical Description:Online Resource
ISSN:1476-4687
DOI:10.1038/s41586-025-08677-w

Similar Items