A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.
A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.
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DOI：
10.1038/s41467-021-25468-9
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发表时间：
2021-09-17
影响因子：
16.6
通讯作者：
Baumert TF
中科院分区：
文献类型：
--
作者：
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
慢性肝病和肝细胞癌（HCC）是威胁生命的疾病，治疗选择有限。缺乏临床相关/易处理的实验模型阻碍了治疗发现。在这里，我们开发了一个简单而强大的基于人类肝细胞的系统，用于模拟临床预后肝脏特征（PLS），预测长期肝病向HCC的进展。使用PLS作为读数，然后在非酒精性脂肪性肝炎/纤维化/HCC动物模型和患者源性肝球状体中进行验证，我们确定了尼扎替丁，一种组胺受体H2（HRH 2）阻滞剂，用于治疗晚期肝病和HCC化学预防。此外，扰动研究结合患者肝组织的单细胞RNA-Seq分析揭示了肝细胞和HRH 2+、CLEC 5A高、MARCO低肝巨噬细胞作为潜在的尼扎替丁靶标。PLS模型与患者组织的单细胞RNA-Seq相结合，能够发现治疗晚期肝病和癌症预防的迫切需要的靶标和治疗方法。由于缺乏合适的临床转化模型，晚期肝病的药物和靶点发现受到阻碍。在这里，作者提出了一个基于人类肝细胞的系统，模拟临床预后特征，允许提出尼扎替丁治疗晚期肝纤维化和肝细胞癌预防。
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. Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.
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影响因子：
25.7
作者：
Fujiwara N;Friedman SL;Goossens N;Hoshida Y
通讯作者：
Hoshida Y
影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.
影响因子：
3.7
作者：
Hoshida Y;Brunet JP;Tamayo P;Golub TR;Mesirov JP
通讯作者：
Mesirov JP
DOI：
10.1016/j.cgh.2015.10.010
发表时间：
2016-11
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
--
作者：
Goossens N;Hoshida Y;Song WM;Jung M;Morel P;Nakagawa S;Zhang B;Frossard JL;Spahr L;Friedman SL;Negro F;Rubbia-Brandt L;Giostra E
通讯作者：
Giostra E
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR