We have shown in the previous funding cycle that we can produce cells from human induced pluripotent stem cells that display most characteristics associated with hepatocytes. The differentiation of the cells is synchronous, reproducible, and highly efficient with 85% of cells in the culture dish assuming a hepatic character. Moreover, iPS cell-derived 'hepatocytes'are metabolically active, are capable of performing most functions associated with mature liver cells, and can engraft into the mouse hepatic parenchyma. We propose that the differentiation of 'hepatocytes'from human iPS cells provides a model to study hepatocyte disease and development. In the current submission we will use this model to identify novel transcriptional regulatory pathways that control the onset of hepatocyte differentiation, and ii) use iPS cells generated from patients to determine whether the hepatocyte dysfunction contributes to the pathophysiology of Maturity Onset Diabetes of the Young (MODY).

Public Health Relevance

We have shown that we can generate liver cells from induced pluripotent stem (iPS) cells that themselves are generated from patient's skin cells. Here we propose to use human iPS cells to identify transcription factors that control liver cell formation. We have also generated iPS cells from skin punch biopsies from patients that suffer from Maturity Onset Diabetes of the Young MODY. We propose to use these cells to determine whether liver function is disrupted in these diabetic patients. The studies will establish the use of iPS cell technology as important tool to study human liver development and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055743-12
Application #
8217247
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2000-06-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
12
Fiscal Year
2012
Total Cost
$332,775
Indirect Cost
$115,275
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Nagaoka, Masato; Kobayashi, Motohiro; Kawai, Chie et al. (2015) Design of a Vitronectin-Based Recombinant Protein as a Defined Substrate for Differentiation of Human Pluripotent Stem Cells into Hepatocyte-Like Cells. PLoS One 10:e0136350
Kolander, Kurt D; Holtz, Mary L; Cossette, Stephanie M et al. (2014) Epicardial GATA factors regulate early coronary vascular plexus formation. Dev Biol 386:204-15
Noto, Fallon K; Determan, Megan R; Cai, Jun et al. (2014) Aneuploidy is permissive for hepatocyte-like cell differentiation from human induced pluripotent stem cells. BMC Res Notes 7:437
Shan, Jing; Schwartz, Robert E; Ross, Nathan T et al. (2013) Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat Chem Biol 9:514-20
Mallanna, Sunil K; Duncan, Stephen A (2013) Differentiation of hepatocytes from pluripotent stem cells. Curr Protoc Stem Cell Biol 26:Unit 1G.4.
Fox, Ira J; Duncan, Stephen A (2013) Engineering liver tissue from induced pluripotent stem cells: a first step in generating new organs for transplantation? Hepatology 58:2198-201
Gundry, Rebekah L; Riordon, Daniel R; Tarasova, Yelena et al. (2012) A cell surfaceome map for immunophenotyping and sorting pluripotent stem cells. Mol Cell Proteomics 11:303-16
Xuan, Shouhong; Borok, Matthew J; Decker, Kimberly J et al. (2012) Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J Clin Invest 122:3516-28
Cayo, Max A; Cai, Jun; DeLaForest, Ann et al. (2012) JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology 56:2163-71
DeLaForest, Ann; Nagaoka, Masato; Si-Tayeb, Karim et al. (2011) HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 138:4143-53

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