Characterization of the role of hepatic stellate cells in liver regeneration
Final Report Abstract
The aim of his research project was to establish a novel mouse model to deplete hepatic stellate cells (HSCs) and to use this model to further elucidate HSCs biology in liver injury and liver regeneration. A combination of biochemical, cell biological and immunological techniques were used to achieve the goals and to address the questions. A novel model for depleting mouse hepatic stellate cells was developed and the contribution of HSCs to liver injury, fibrosis and regeneration analyzed. Transgenic mice expressing the herpes simplex virus thymidine kinase driven by the mouse GFAP promoter were shown to be HSC specific and to render HSC susceptible to cell killing by administration of ganciclovir. Two different liver injury models were used to induce proliferation of HSCs and depletion of HSCs verified by dual immunfluorescence for desmin and GFAP as well as subsequent quantification. Depletion of HSCs in transgenic mice (Tg) led to attenuated fibrosis and reduced liver injury as assessed by Sirius red/Fast green staining and morphometry as well as histological scoring and serum analysis for AST/ALT. Partial hepatectomy as model for liver regeneration revealed impaired liver regeneration in Tg mice as assessed by staining for proliferation markers and analysis of liver to body weight ratio. Thus, activated HSCs significantly amplify the response to liver injury and enhance liver regeneration. This has important implications for onging therapeutic approaches to target HSCs for antifibrotic therapies. The novel model for depleting mouse HSCs will offer a valuable tool to analyze further important questions in HSC biology.
Publications
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(2010). Fibrosis in the Liver: acute protection and chronic disease. Prog Mol Biol Transl Sci. 2010;97:151-200
Lee, YM. and Friedman SL.
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(2012) A Novel Murine Model to Deplete Hepatic Stellate Cells Uncovers Their Role In Amplifying Liver Damage. Hepatology. 2012 Sep 7 [Epub ahead of print]
Puche JE, Lee YA, Jiao JJ, Aloman C, Fiel MI, Munoz U, Kraus T, Lee TF, Yee H, Friedman SL
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Pathobiology of liver Fibrosis: a translational success story. GUT 2015
Lee YA, Wallace MC, Friedman SL.
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Reversal, maintenance or progression: What happens to the liver after a virologic cure of hepatitis C?, Antiviral Res 2014. 107C:23–30
Lee, YA, Friedman, SL.
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Epithelial XBP1 is Required for Cellular Proliferation and Differentiation During Mammary Gland Development, Mol Cell Biol Molecular and Cellular Biology Apr 2015, 35 (9) 1543-1556
Hasegawa, D., Calvo, V., Avivar-Valderas. A., Lade, A., Chou, H., Lee, YA., Farias, EF., Aguirre-Ghiso, JA., Friedman, SL.
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β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol Volume 63, Issue 1, July 2015, Pages 141-147
Kocabayoglu P, Lade, A, Lee, YA., Dragomir, A I Fiel, MI; Thung, S., Aloman, C., Soriano, P., Hoshida, Y., Friedman, SL.
