The capacity of embryonic stem (ES) cells to differentiate to hepatocytes in culture provides a unique model system to study alcohol-induced liver injury in vitro, and ultimately to provide large amount of mature hepatocytes for transplantation in liver failure due to chronic alcoholic liver disease. Liver develops from the gut endoderm along with other major organs including the pancreas, lungs, thyroid and intestines. The experiments outlined in the proposal build on previous observations that endoderm-derived hepatoblast-like cells can be efficiently and reproducibly induced in the mouse ES cell system and seek to translate the murine ES cell differentiation program to the human ES cell program""""""""!. This application addresses questions relating to maturation of mouse ES-derived hepatoblast-like cells, to the endoderm induction in the human ES cell system and its specification to a hepatic fate and finally to mature human hepatocytes. Therefore, the ultimate goal of these studies is to develop a feasible approach to generate functional hepatocytes from mouse and human ES cells as an in vitro model to study alcohol-induced liver injury.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory Grants (P20)
Project #
5P20AA017067-05
Application #
8380260
Study Section
Special Emphasis Panel (ZAA1-BB)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$37,378
Indirect Cost
$15,326
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Arriazu, Elena; Ge, Xiaodong; Leung, Tung-Ming et al. (2017) Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut 66:1123-1137
Renault, Thibaud T; Luna-Vargas, Mark P A; Chipuk, Jerry E (2016) Mouse Liver Mitochondria Isolation, Size Fractionation, and Real-time MOMP Measurement. Bio Protoc 6:
Kocabayoglu, Peri; Lade, Abigale; Lee, Youngmin A et al. (2015) ?-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol 63:141-7
Renault, Thibaud T; Floros, Konstantinos V; Elkholi, Rana et al. (2015) Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis. Mol Cell 57:69-82
Hasegawa, Daisuke; Calvo, Veronica; Avivar-Valderas, Alvaro et al. (2015) Epithelial Xbp1 is required for cellular proliferation and differentiation during mammary gland development. Mol Cell Biol 35:1543-56
Lu, Yongke; Ward, Stephen C; Nieto, Natalia (2014) Ethanol plus the Jo2 Fas agonistic antibody-induced liver injury is attenuated in mice with partial ablation of argininosuccinate synthase. Alcohol Clin Exp Res 38:649-56
Lade, Abigale; Noon, Luke A; Friedman, Scott L (2014) Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer. Curr Opin Oncol 26:100-7
Jiao, Jingjing; Dragomir, Ana-Cristina; Kocabayoglu, Peri et al. (2014) Central role of conventional dendritic cells in regulation of bone marrow release and survival of neutrophils. J Immunol 192:3374-82
Renault, Thibaud T; Elkholi, Rana; Bharti, Archana et al. (2014) B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins. J Biol Chem 289:26481-91
Howarth, Deanna L; Lindtner, Claudia; Vacaru, Ana M et al. (2014) Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet 10:e1004335

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