Hepatic stellate cells control liver zonation, size and functions via Rspo3

Atsushi Sugimoto; Yoshinobu Saito; Guanxiong Wang; Quiyan  Sun; Chuan Lin; Ki Hong Lee; Yana Geng; Presha Rajbhandari; Celine Hernandez; Marcella Steffani; Jingran Qie; Thomas Savage; Dhrub M. Goyal; Kevin C. Ray; Taruna V. Neelakantan; Deqi Yin; Johannes Melms; Brandom 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

doi:10.1038/s41586-025-08677-w

Hepatic stellate cells control liver zonation, size and functions via Rspo3

Atsushi Sugimoto, Yoshinobu Saito, Guanxiong Wang, Quiyan Sun, Chuan Lin, Ki Hong Lee, Yana Geng, Presha Rajbhandari, Celine Hernandez, Marcella Steffani, Jingran Qie, Thomas Savage, Dhrub M. Goyal, Kevin C. Ray, Taruna V. Neelakantan, Deqi Yin, Johannes Melms, Brandom M. Lehrich, Tyler M. Yasaka, Silvia LiuMichael 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

Research output: Contribution to journal › Article › peer-review

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 understood 1-5. 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.

Original language	English
Article number	2823
Pages (from-to)	752-761
Journal	Nature
Volume	640
DOIs	https://doi.org/10.1038/s41586-025-08677-w
Publication status	Published - 12 Mar 2025

Keywords / Materials (for Non-textual outputs)

Animals
Fatty Liver/pathology
Female
Hepatic Stellate Cells/metabolism
Hepatocytes/metabolism
Humans
Liver Regeneration
Liver/cytology
Male
Mice
Organ Size
R-Spondins
Thrombospondins/metabolism
Wnt Signaling Pathway

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10.1038/s41586-025-08677-w

Manuscript 2024-02-04354B 12Jan2025_Jonathan FallowfieldAccepted author manuscript, 357 KB
s41586-025-08677-wFinal published version, 90.4 MB

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Sugimoto, A., Saito, Y., Wang, G., Sun, Q., Lin, C., Lee, K. H., Geng, Y., Rajbhandari, P., Hernandez, C., Steffani, M., Qie, J., Savage, T., Goyal, D. M., Ray, K. C., Neelakantan, T. V., Yin, D., Melms, J., Lehrich, B. M., Yasaka, T. M., ... Schwabe, R. F. (2025). Hepatic stellate cells control liver zonation, size and functions via Rspo3. Nature, 640, 752-761. Article 2823. https://doi.org/10.1038/s41586-025-08677-w

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title = "Hepatic stellate cells control liver zonation, size and functions via Rspo3",

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 understood 1-5. 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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author = "Atsushi Sugimoto and Yoshinobu Saito and Guanxiong Wang and Quiyan Sun and Chuan Lin and Lee, {Ki Hong} and Yana Geng and Presha Rajbhandari and Celine Hernandez and Marcella Steffani and Jingran Qie and Thomas Savage and Goyal, {Dhrub M.} and Ray, {Kevin C.} and Neelakantan, {Taruna V.} and Deqi Yin and Johannes Melms and Lehrich, {Brandom M.} and Yasaka, {Tyler M.} and Silvia Liu and Michael Oertel and Tian Lan and Adrien Guillot and Moritz Peiseler and Aveline Filliol and Hiroaki Kanzaki and Naoto Fujiwara and Samhita Ravi and Benjamin Izar and Mario Brosch and Jochen Hampe and Helen Remotti and Josepmaria Argemi and Zhaoli Sun and Kendall, {Timothy J.} and Yujin Hoshida and Frank Tacke and Fallowfield, {Jonathan A} and Blockley-Powell, {Storm K.} and Haeusler, {Rebecca A.} and Steinman, {Jonathan B.} and Pajvani, {Utpal B.} and Monga, {Satdarshan P} and Ramon Bataller and Mojgan Masoodi and Nicholas Arpaia and Lee, {Youngmin A.} and Stockwell, {Brent R.} and Augustin, {Hellmut G} and Schwabe, {Robert F}",

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month = mar,

day = "12",

doi = "10.1038/s41586-025-08677-w",

language = "English",

volume = "640",

pages = "752--761",

journal = "Nature",

issn = "0028-0836",

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Sugimoto, A, Saito, Y, Wang, G, Sun, Q, Lin, C, Lee, KH, Geng, Y, Rajbhandari, P, Hernandez, C, Steffani, M, Qie, J, Savage, T, Goyal, DM, Ray, KC, Neelakantan, TV, Yin, D, Melms, J, Lehrich, BM, Yasaka, TM, Liu, S, Oertel, M, Lan, T, Guillot, A, Peiseler, M, Filliol, A, Kanzaki, H, Fujiwara, N, Ravi, S, Izar, B, Brosch, M, Hampe, J, Remotti, H, Argemi, J, Sun, Z, Kendall, TJ, Hoshida, Y, Tacke, F, Fallowfield, JA, Blockley-Powell, SK, Haeusler, RA, Steinman, JB, Pajvani, UB, Monga, SP, Bataller, R, Masoodi, M, Arpaia, N, Lee, YA, Stockwell, BR, Augustin, HG & Schwabe, RF 2025, 'Hepatic stellate cells control liver zonation, size and functions via Rspo3', Nature, vol. 640, 2823, pp. 752-761. https://doi.org/10.1038/s41586-025-08677-w

TY - JOUR

T1 - Hepatic stellate cells control liver zonation, size and functions via Rspo3

AU - Sugimoto, Atsushi

AU - Saito, Yoshinobu

AU - Wang, Guanxiong

AU - Sun, Quiyan

AU - Lin, 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, Dhrub M.

AU - Ray, Kevin C.

AU - Neelakantan, Taruna V.

AU - Yin, Deqi

AU - Melms, Johannes

AU - Lehrich, Brandom 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 G

AU - Schwabe, Robert F

PY - 2025/3/12

Y1 - 2025/3/12

N2 - Hepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood 1-5. 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.

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 understood 1-5. 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.

KW - Animals

KW - Fatty Liver/pathology

KW - Female

KW - Hepatic Stellate Cells/metabolism

KW - Hepatocytes/metabolism

KW - Humans

KW - Liver Regeneration

KW - Liver/cytology

KW - Male

KW - Mice

KW - Organ Size

KW - R-Spondins

KW - Thrombospondins/metabolism

KW - Wnt Signaling Pathway

U2 - 10.1038/s41586-025-08677-w

DO - 10.1038/s41586-025-08677-w

M3 - Article

C2 - 40074890

SN - 0028-0836

VL - 640

SP - 752

EP - 761

JO - Nature

JF - Nature

M1 - 2823

ER -

Hepatic stellate cells control liver zonation, size and functions via Rspo3

Abstract

Keywords / Materials (for Non-textual outputs)

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