We have previously described a protocol that allows us to efficiently and reproducibly convert human iPSCs into cells that share most of the characteristics of hepatocytes. We have published our success in using patient specific iPSCs to model infectious liver disease, inborn errors of hepatic metabolism, and early cell fate decisions. The procedure uses wholly defined conditions and as a consequence results in a synchronous differentiation that appears to closely mirror the known development events that occur during normal hepatocyte formation. In the submitted proposal we propose to use this human model to uncover the molecular mechanisms through which hepatic progenitor cells are generated from definitive endoderm. Specification of the hepatic progenitors has historically been recalcitrant to molecular analysis because the process is dynamic and hepatic progenitor cells are a transient population that are difficult to access in quantity in model organisms. Because the formation of the hepatic progenitors from iPSCs is synchronous and reproducible it affords access to a cell population that is amenable to genetic manipulation and molecular and biochemical analyses. We propose to exploit this to define the molecular events that link signaling molecules that act on the endoderm to the action of transcription factors that define the generation of hepatic progenitor cells. We believe that success in the proposal will significantly advance our understanding of the fundamental molecular basis of hepatocyte formation and help realize the full potential of stem cells in the study and treatment of liver disease.
We have shown previously that we can produce liver cells, called hiHeps, from human induced pluripotent stem cells (hiPSCs) that themselves are generated by reprogramming skin cells. The hiHeps are produced by encouraging iPSCs to follow the normal developmental program that occurs during embryonic development to produce liver cells. As a consequence we can use this cell culture model to unravel the complex molecular mechanisms that underlie human liver development. This is important because it will help us to produce liver cells that can be used to study inborn errors of hepatic metabolism and possibly allow the identification of methods that can be used to correct such diseases. The proposed experiments are designed to reveal the molecular events that convert human endoderm to hepatic progenitor cells.
|Heslop, James A; Duncan, Stephen A (2018) The use of human pluripotent stem cells for modelling liver development and disease. Hepatology :|
|Jing, Ran; Corbett, James L; Cai, Jun et al. (2018) A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome. Cell Rep 25:1469-1484.e5|
|Liu, Jui-Tung; Lamprecht, Mary Paige; Duncan, Stephen A (2018) Using Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells for Drug Discovery. J Vis Exp :|
|Bi, Xin; Pashos, Evanthia E; Cuchel, Marina et al. (2017) ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion. EBioMedicine 18:139-145|
|Jing, Ran; Duncan, Cameron B; Duncan, Stephen A (2017) A small-molecule screen reveals that HSP90? promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover. Development 144:1764-1774|
|Pashos, Evanthia E; Park, YoSon; Wang, Xiao et al. (2017) Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci. Cell Stem Cell 20:558-570.e10|
|Liu, Ying; Conlon, Donna M; Bi, Xin et al. (2017) Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress. Cell Rep 19:1456-1466|
|Fisher, J B; Pulakanti, K; Rao, S et al. (2017) GATA6 is essential for endoderm formation from human pluripotent stem cells. Biol Open 6:1084-1095|
|Cayo, Max A; Mallanna, Sunil K; Di Furio, Francesca et al. (2017) A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia. Cell Stem Cell 20:478-489.e5|
|Pournasr, Behshad; Duncan, Stephen A (2017) Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells. Arterioscler Thromb Vasc Biol 37:1994-1999|
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