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).
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.
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|Si-Tayeb, Karim; Lemaigre, Frederic P; Duncan, Stephen A (2010) Organogenesis and development of the liver. Dev Cell 18:175-89|
|Sepac, Ana; Sedlic, Filip; Si-Tayeb, Karim et al. (2010) Isoflurane preconditioning elicits competent endogenous mechanisms of protection from oxidative stress in cardiomyocytes derived from human embryonic stem cells. Anesthesiology 113:906-16|
|Si-Tayeb, Karim; Noto, Fallon K; Sepac, Ana et al. (2010) Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev Biol 10:81|
|Sun, Kai; Battle, Michele A; Misra, Ravi P et al. (2009) Hepatocyte expression of serum response factor is essential for liver function, hepatocyte proliferation and survival, and postnatal body growth in mice. Hepatology 49:1645-54|
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