Publicaciones científicas
- [ESTRÉS CELULAR E INMUNOTERAPIA EN CÁNCER HEPÁTICO]
- [BIOLOGIA Y TERAPIA DE ARN]
- [TERAPIAS DE ADN Y ARN]
Hepatic stellate cells control liver zonation, size and functions via R-spondin 3
Atsushi Sugimoto # 1 2, Yoshinobu Saito # 1 2 3, Guanxiong Wang # 4 5, Qiuyan Sun 1 2, Chuan Yin 1 2, Ki Hong Lee 4 5, Yana Geng 1 2, Presha Rajbhandari 6, Celine Hernandez 1 2, Marcella Steffani 1 2, Jingran Qie 1 2, Thomas Savage 7, Dhruv M Goyal 1 2, Kevin C Ray 8, Taruna V Neelakantan 6, Deqi Yin 1 2, Johannes Melms 1, Brandon M Lehrich 9, Tyler M Yasaka 9, Silvia Liu 9, Michael Oertel 9, Tian Lan 10, Adrien Guillot 10, Moritz Peiseler 10, Aveline Filliol 1 2, Hiroaki Kanzaki 11, Naoto Fujiwara 11, Samhita Ravi 12, Benjamin Izar 1 13 14, Mario Brosch 15, Jochen Hampe 15, Helen Remotti 2 16, Josepmaria Argemi 17 18, Zhaoli Sun 19, Timothy J Kendall 20, Yujin Hoshida 11, Frank Tacke 10, Jonathan A Fallowfield 20, Storm K Blockley-Powell 1 2, Rebecca A Haeusler 1 2, Jonathan B Steinman 21, Utpal B Pajvani 1 2 22, Satdarshan P Monga 9, Ramon Bataller 23, Mojgan Masoodi 24, Nicholas Arpaia 2 13 14, Youngmin A Lee 8, Brent R Stockwell 2 6 14, Hellmut G Augustin 25 26, Robert F Schwabe 27 28 29 30 31 32
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.
CITA DEL ARTÍCULO Nature. 2025 Apr;640(8059):752-761. doi: 10.1038/s41586-025-08677-w. Epub 2025 Mar 12.
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