A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

Emilie Crouchet; Simonetta Bandiera; Naoto Fujiwara; Shen Li; Hussein El Saghire; Mirian Fernández-Vaquero; Tobias Riedl; Xiaochen Sun; Hadassa Hirschfield; Frank Jühling; Shijia Zhu; Natascha Roehlen; Clara Ponsolles; Laura Heydmann; Antonio Saviano; Tongqi Qian; Anu Venkatesh; Joachim Lupberger; Eloi R. Verrier; Mozhdeh Sojoodi; Marine A. Oudot; François H.T. Duong; Ricard Masia; Lan Wei; Christine Thumann; Sarah C. Durand; Victor González-Motos; Danijela Heide; Jenny Hetzer; Shigeki Nakagawa; Atsushi Ono; Won Min Song; Takaaki Higashi; Roberto Sanchez; Rosa S. Kim; C. Billie Bian; Karun Kiani; Tom Croonenborghs; Aravind Subramanian; Raymond T. Chung; Beate K. Straub; Detlef Schuppan; Maliki Ankavay; Laurence Cocquerel; Evelyne Schaeffer; Nicolas Goossens; Anna P. Koh; Milind Mahajan; Venugopalan D. Nair; Ganesh Gunasekaran; Myron E. Schwartz; Nabeel Bardeesy; Alex K. Shalek; Orit Rozenblatt-Rosen; Aviv Regev; Emanuele Felli; Patrick Pessaux; Kenneth K. Tanabe; Mathias Heikenwälder; Catherine Schuster; Nathalie Pochet; Mirjam B. Zeisel; Bryan C. Fuchs; Yujin Hoshida; Thomas F. Baumert

doi:10.1038/s41467-021-25468-9

A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

Emilie Crouchet, Simonetta Bandiera, Naoto Fujiwara, Shen Li, Hussein El Saghire, Mirian Fernández-Vaquero, Tobias Riedl, Xiaochen Sun, Hadassa Hirschfield, Frank Jühling, Shijia Zhu, Natascha Roehlen, Clara Ponsolles, Laura Heydmann, Antonio Saviano, Tongqi Qian, Anu Venkatesh, Joachim Lupberger, Eloi R. Verrier, Mozhdeh SojoodiMarine A. Oudot, François H.T. Duong, Ricard Masia, Lan Wei, Christine Thumann, Sarah C. Durand, Victor González-Motos, Danijela Heide, Jenny Hetzer, Shigeki Nakagawa, Atsushi Ono, Won Min Song, Takaaki Higashi, Roberto Sanchez, Rosa S. Kim, C. Billie Bian, Karun Kiani, Tom Croonenborghs, Aravind Subramanian, Raymond T. Chung, Beate K. Straub, Detlef Schuppan, Maliki Ankavay, Laurence Cocquerel, Evelyne Schaeffer, Nicolas Goossens, Anna P. Koh, Milind Mahajan, Venugopalan D. Nair, Ganesh Gunasekaran, Myron E. Schwartz, Nabeel Bardeesy, Alex K. Shalek, Orit Rozenblatt-Rosen, Aviv Regev, Emanuele Felli, Patrick Pessaux, Kenneth K. Tanabe, Mathias Heikenwälder, Catherine Schuster, Nathalie Pochet, Mirjam B. Zeisel, Bryan C. Fuchs, Yujin Hoshida, Thomas F. Baumert

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18 Scopus citations

Abstract

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2⁺, CLEC5A^high, MARCO^low liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

Original language	English (US)
Article number	5525
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25468-9
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Crouchet, E., Bandiera, S., Fujiwara, N., Li, S., El Saghire, H., Fernández-Vaquero, M., Riedl, T., Sun, X., Hirschfield, H., Jühling, F., Zhu, S., Roehlen, N., Ponsolles, C., Heydmann, L., Saviano, A., Qian, T., Venkatesh, A., Lupberger, J., Verrier, E. R., ... Baumert, T. F. (2021). A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery. Nature communications, 12(1), Article 5525. https://doi.org/10.1038/s41467-021-25468-9

Crouchet, E, Bandiera, S, Fujiwara, N, Li, S, El Saghire, H, Fernández-Vaquero, M, Riedl, T, Sun, X, Hirschfield, H, Jühling, F, Zhu, S, Roehlen, N, Ponsolles, C, Heydmann, L, Saviano, A, Qian, T, Venkatesh, A, Lupberger, J, Verrier, ER, Sojoodi, M, Oudot, MA, Duong, FHT, Masia, R, Wei, L, Thumann, C, Durand, SC, González-Motos, V, Heide, D, Hetzer, J, Nakagawa, S, Ono, A, Song, WM, Higashi, T, Sanchez, R, Kim, RS, Bian, CB, Kiani, K, Croonenborghs, T, Subramanian, A, Chung, RT, Straub, BK, Schuppan, D, Ankavay, M, Cocquerel, L, Schaeffer, E, Goossens, N, Koh, AP, Mahajan, M, Nair, VD, Gunasekaran, G, Schwartz, ME, Bardeesy, N, Shalek, AK, Rozenblatt-Rosen, O, Regev, A, Felli, E, Pessaux, P, Tanabe, KK, Heikenwälder, M, Schuster, C, Pochet, N, Zeisel, MB, Fuchs, BC, Hoshida, Y & Baumert, TF 2021, 'A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery', Nature communications, vol. 12, no. 1, 5525. https://doi.org/10.1038/s41467-021-25468-9

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title = "A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery",

abstract = "Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.",

author = "Emilie Crouchet and Simonetta Bandiera and Naoto Fujiwara and Shen Li and {El Saghire}, Hussein and Mirian Fern{\'a}ndez-Vaquero and Tobias Riedl and Xiaochen Sun and Hadassa Hirschfield and Frank J{\"u}hling and Shijia Zhu and Natascha Roehlen and Clara Ponsolles and Laura Heydmann and Antonio Saviano and Tongqi Qian and Anu Venkatesh and Joachim Lupberger and Verrier, {Eloi R.} and Mozhdeh Sojoodi and Oudot, {Marine A.} and Duong, {Fran{\c c}ois H.T.} and Ricard Masia and Lan Wei and Christine Thumann and Durand, {Sarah C.} and Victor Gonz{\'a}lez-Motos and Danijela Heide and Jenny Hetzer and Shigeki Nakagawa and Atsushi Ono and Song, {Won Min} and Takaaki Higashi and Roberto Sanchez and Kim, {Rosa S.} and Bian, {C. Billie} and Karun Kiani and Tom Croonenborghs and Aravind Subramanian and Chung, {Raymond T.} and Straub, {Beate K.} and Detlef Schuppan and Maliki Ankavay and Laurence Cocquerel and Evelyne Schaeffer and Nicolas Goossens and Koh, {Anna P.} and Milind Mahajan and Nair, {Venugopalan D.} and Ganesh Gunasekaran and Schwartz, {Myron E.} and Nabeel Bardeesy and Shalek, {Alex K.} and Orit Rozenblatt-Rosen and Aviv Regev and Emanuele Felli and Patrick Pessaux and Tanabe, {Kenneth K.} and Mathias Heikenw{\"a}lder and Catherine Schuster and Nathalie Pochet and Zeisel, {Mirjam B.} and Fuchs, {Bryan C.} and Yujin Hoshida and Baumert, {Thomas F.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-25468-9",

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T1 - A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

AU - Crouchet, Emilie

AU - Bandiera, Simonetta

AU - Fujiwara, Naoto

AU - Li, Shen

AU - El Saghire, Hussein

AU - Fernández-Vaquero, Mirian

AU - Riedl, Tobias

AU - Sun, Xiaochen

AU - Hirschfield, Hadassa

AU - Jühling, Frank

AU - Zhu, Shijia

AU - Roehlen, Natascha

AU - Ponsolles, Clara

AU - Heydmann, Laura

AU - Saviano, Antonio

AU - Qian, Tongqi

AU - Venkatesh, Anu

AU - Lupberger, Joachim

AU - Verrier, Eloi R.

AU - Sojoodi, Mozhdeh

AU - Oudot, Marine A.

AU - Duong, François H.T.

AU - Masia, Ricard

AU - Wei, Lan

AU - Thumann, Christine

AU - Durand, Sarah C.

AU - González-Motos, Victor

AU - Heide, Danijela

AU - Hetzer, Jenny

AU - Nakagawa, Shigeki

AU - Ono, Atsushi

AU - Song, Won Min

AU - Higashi, Takaaki

AU - Sanchez, Roberto

AU - Kim, Rosa S.

AU - Bian, C. Billie

AU - Kiani, Karun

AU - Croonenborghs, Tom

AU - Subramanian, Aravind

AU - Chung, Raymond T.

AU - Straub, Beate K.

AU - Schuppan, Detlef

AU - Ankavay, Maliki

AU - Cocquerel, Laurence

AU - Schaeffer, Evelyne

AU - Goossens, Nicolas

AU - Koh, Anna P.

AU - Mahajan, Milind

AU - Nair, Venugopalan D.

AU - Gunasekaran, Ganesh

AU - Schwartz, Myron E.

AU - Bardeesy, Nabeel

AU - Shalek, Alex K.

AU - Rozenblatt-Rosen, Orit

AU - Regev, Aviv

AU - Felli, Emanuele

AU - Pessaux, Patrick

AU - Tanabe, Kenneth K.

AU - Heikenwälder, Mathias

AU - Schuster, Catherine

AU - Pochet, Nathalie

AU - Zeisel, Mirjam B.

AU - Fuchs, Bryan C.

AU - Hoshida, Yujin

AU - Baumert, Thomas F.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

AB - Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

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DO - 10.1038/s41467-021-25468-9

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VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

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ER -

A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

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