TY  - JOUR
AU  - Sugimoto, Atsushi
AU  - Saito, Yoshinobu
AU  - Wang, Guanxiong
AU  - Sun, Qiuyan
AU  - Yin, Chuan
AU  - Lee, Ki Hong
AU  - Geng, Yana
AU  - Rajbhandari, Presha
AU  - Hernandez, Celine
AU  - Steffani, Marcella
AU  - Qie, Jingran
AU  - Savage, Thomas
AU  - Goyal, Dhruv M
AU  - Ray, Kevin C
AU  - Neelakantan, Taruna V
AU  - Yin, Deqi
AU  - Melms, Johannes
AU  - Lehrich, Brandon M
AU  - Yasaka, Tyler M
AU  - Liu, Silvia
AU  - Oertel, Michael
AU  - Lan, Tian
AU  - Guillot, Adrien
AU  - Peiseler, Moritz
AU  - Filliol, Aveline
AU  - Kanzaki, Hiroaki
AU  - Fujiwara, Naoto
AU  - Ravi, Samhita
AU  - Izar, Benjamin
AU  - Brosch, Mario
AU  - Hampe, Jochen
AU  - Remotti, Helen
AU  - Argemi, Josepmaria
AU  - Sun, Zhaoli
AU  - Kendall, Timothy J
AU  - Hoshida, Yujin
AU  - Tacke, Frank
AU  - Fallowfield, Jonathan A
AU  - Blockley-Powell, Storm K
AU  - Haeusler, Rebecca A
AU  - Steinman, Jonathan B
AU  - Pajvani, Utpal B
AU  - Monga, Satdarshan P
AU  - Bataller, Ramon
AU  - Masoodi, Mojgan
AU  - Arpaia, Nicholas
AU  - Lee, Youngmin A
AU  - Stockwell, Brent R
AU  - Augustin, Hellmut
AU  - Schwabe, Robert F
TI  - Hepatic stellate cells control liver zonation, size and functions via R-spondin 3.
JO  - Nature
VL  - 640
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2025-00540
SP  - 752–761
PY  - 2025
N1  - #EA:A190# / 640, pages 752–761 (2025)
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40074890
DO  - DOI:10.1038/s41586-025-08677-w
UR  - https://inrepo02.dkfz.de/record/299785
ER  -