Recent progress in human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) research opens up unprecedented opportunities for the development of new strategies to repair and replace organs including liver. It is also highly desirable to establish disease models using patient specific iPS cells derived from the diseased tissues that contain somatic mutations which are not present in other tissues or in healthy individuals. Hepatocarcinogenesis is considered as a multi-step process involving a number of different genetic alterations caused by environmental factors such as alcohol. The accumulated effects ultimately lead to malignant transformation of hepatocytes. The molecular events underlying each step of the process are not fully understood and better model systems are needed to delineate the mechanism. Complimentary to current available models, iPS technology offers unique opportunity to preserve and study cells at various disease stages that lead to hepatocellular carcinoma (HCC). Towards the goal of studying liver diseases using pluripotent stem cells, we have systematically improved reprogramming of human postnatal cells including primary hepatocytes.Importantly, we were able to differentiate iPS cells into early and mature hepatic cells. In this study, we propose to explore the possibility of modeling alcohol related HCC using patient- and disease- specific iPS cells. We plan to generate iPS cell lines from liver tissues of HCC patients with chronic alcohol consumption history. After characterization of these iPS cell lines, we will differentiate them into different stages of hepatic cells, using iPS cells from healthy donors as controls. We will test the hypothesis that the hepatic cells generated from diseased iPS cells possess certain characteristics of the disease (i.e. HCC). In particular, their ability to terminally differentiate, to proliferate and to undergo apoptosis will be determined. We will also initiate transplantation of these iPSC derived hepatic cells into immunodeficient mice to determine the in vivo activity of the cells. Completion of this study will help establish more human HCC relevant, innovative in vitro and in vivo models to systematically study the molecular mechanisms and the contribution of alcohol and other risk factors to different stages of hepatocarcinogenesis.
Completion of this study will help establish more human HCC relevant, innovative in vitro and in vivo models to systematically study the molecular mechanisms and the contribution of alcohol and other risk factors to different stages of hepatocarcinogenesis.
|Chaudhari, Pooja; Tian, Lipeng; Deshmukh, Abhijeet et al. (2016) Expression kinetics of hepatic progenitor markers in cellular models of human liver development recapitulating hepatocyte and biliary cell fate commitment. Exp Biol Med (Maywood) 241:1653-62|
|Tian, Lipeng; Deshmukh, Abhijeet; Prasad, Neha et al. (2016) Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells. Int J Biol Sci 12:1052-62|
|Tian, Lipeng; Deshmukh, Abhijeet; Ye, Zhaohui et al. (2016) Efficient and Controlled Generation of 2D and 3D Bile Duct Tissue from Human Pluripotent Stem Cell-Derived Spheroids. Stem Cell Rev 12:500-8|
|Chaudhari, Pooja; Prasad, Neha; Tian, Lipeng et al. (2016) Determination of Functional Activity of Human iPSC-Derived Hepatocytes by Measurement of CYP Metabolism. Methods Mol Biol 1357:383-94|
|Tian, Lipeng; Prasad, Neha; Jang, Yoon-Young (2016) In Vitro Modeling of Alcohol-Induced Liver Injury Using Human-Induced Pluripotent Stem Cells. Methods Mol Biol 1353:271-83|
|Kurbanov, Fuat; Kim, Yonghak; Latanich, Rachel et al. (2015) IFNL3 genotype is associated with differential induction of IFNL3 in primary human hepatocytes. Antivir Ther 20:805-14|
|Chaudhari, Pooja; Ye, Zhaohui; Jang, Yoon-Young (2014) Roles of reactive oxygen species in the fate of stem cells. Antioxid Redox Signal 20:1881-90|
|Choi, Su Mi; Kim, Yonghak; Shim, Joong Sup et al. (2013) Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells. Hepatology 57:2458-68|
|Sharkis, Saul J; Jones, Richard J; Civin, Curt et al. (2012) Pluripotent stem cell-based cancer therapy: promise and challenges. Sci Transl Med 4:127ps9|
|Choi, Su Mi; Kim, Yonghak; Liu, Hua et al. (2011) Liver engraftment potential of hepatic cells derived from patient-specific induced pluripotent stem cells. Cell Cycle 10:2423-7|
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