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| Home > Publications database > Hepatic stellate cells control liver zonation, size and functions via R-spondin 3. |
| Home > Publications database > Hepatic stellate cells control liver zonation, size and functions via R-spondin 3. |
| Journal Article | DKFZ-2025-00540 |
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2025
Nature Publ. Group
London [u.a.]
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Please use a persistent id in citations: doi:10.1038/s41586-025-08677-w
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.
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