Hepatic stellate cells control liver zonation, size and functions via R-spondin 3
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.
Article Details
Authors (50)
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 Argemí
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