Nature communications · 2021

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен

Обработка статьи · этапы, ошибки и управление

Загрузка состояния…

История · было → стало

Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.

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

Аннотация

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.

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH