End-stage liver cirrhosis is one of the most common causes of mortality in modern countries and can only be treated by liver transplantation, which is strongly limited by the lack of organ donors and the side effects of immunosuppressive treatment. Therefore, the development of new therapeutics against liver diseases represents a global health challenge and one of the main objective for the pharmaceutical industry.
However, the lack of relevant, physiological and high throughput in vitro system to model liver fibrosis represents a major issue. Current in vitro models of the fibrotic liver consist in cell cultures, precision slice biopsies, and whole organ perfusion systems. 2D culture systems lack functional cell-to-cell interactions and anatomical structures needed to reveal mechanistic details of disease involved in fibrosis, while perfusion and biopsy based models cannot persist long enough to accurately model fibrotic progression. Consequently, most studies are based on animal models which can lack the physiological relevance to human diseases and which are not compatible with high throughput platform necessary for drug screening.
Here, we propose to use of human Induced Pluripotent Stem Cells (hIPSCs) to establish an in vitro model for liver fibrosis. For that, hIPSCs will be differentiated into cell types relevant for the disease including hepatocytes, macrophages, cholangiocytes, and stellate cells. The resulting cells will embedded in a 3-D scaffold-based culture system compatible with high trough put analyses. Then different etiologies will be modeled including liver fibrosis induced by ethanol, tetrachloride and alpha-1 antitrypsin deficiency. The resulting system will be validated by direct comparison with results obtained in mouse model for liver injury. This project will pave the way for the development of new in vitro model for the study of fibrosis in a diversity of organs and will ultimately allow the development of new therapies.
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