Abstract

In the previous funding cycle, we examined the mechanism through which FGF and BMP specify the endoderm to adopt a hepatic fate. We revealed that FGF has a critical role in controlling expression of a WNT inhibitor called NKD1. NKD1 transiently suppresses WNT activity, which is needed to promote hepatic fate. BMP controls hepatic fate through activation of SMAD1. This signaling pathway regulates expression of several developmental regulators. Like FGF, BMP induces NKD1. BMP also controls expression of several regulators of chromatin structure including TFAP2A and ARID5B. In the current proposal, we will study the roles of TFAP2A and ARID5B in generating hepatic progenitor cells. We had also had previously shown that GATA6 is necessary for hepatic specification in mouse embryos. We, therefore, propose to determine the mechanism through which GATA6 controls hepatic fate. We hypothesize that GATA6 acts as a pioneer transcription factor to promote the competency of the endoderm to respond to inductive cues.

Public Health Relevance

We will use human induced pluripotent stem cells (iPSCs) as a model to understand the fundamental mechanisms through which the liver is formed. We will determine whether GATA6 acts as a pioneer factor to open chromatin around liver enhancers. We will also determine whether two BMP4 immediate early target genes, TFAP2A and ARID5B, are needed for the formation of liver cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK102716-06A1
Application #
9886459
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2014-07-01
Project End
2023-06-30
Budget Start
2019-09-23
Budget End
2020-06-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29407

  Publications

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 :
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
Mallanna, Sunil K; Waas, Matthew; Duncan, Stephen A et al. (2017) N-glycoprotein surfaceome of human induced pluripotent stem cell derived hepatic endoderm. Proteomics 17:
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

Showing the most recent 10 out of 14 publications