The generation of functional hepatocytes independent of donor liver organs is of great therapeutic interest with regard to regenerative medicine and possible cures for liver disease1. Induced hepatic differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells2,3,4,5,6,7,8. Particularly, hepatocytes generated from a patient’s own induced pluripotent stem cells could theoretically avoid immunological rejection. However, the induction of hepatocytes from induced pluripotent stem cells is a complicated process that would probably be replaced with the arrival of improved technology. Overexpression of lineage-specific transcription factors directly converts terminally differentiated cells into some other lineages9,10,11,12, including neurons13, cardiomyocytes14 and blood progenitors15; however, it remains unclear whether these lineage-converted cells could repair damaged tissues in vivo. Here we demonstrate the direct induction of functional hepatocyte-like (iHep) cells from mouse tail-tip fibroblasts by transduction of Gata4, Hnf1α and Foxa3, and inactivation of p19Arf. iHep cells show typical epithelial morphology, express hepatic genes and acquire hepatocyte functions. Notably, transplanted iHep cells repopulate the livers of fumarylacetoacetate-hydrolase-deficient (Fah−/−) mice and rescue almost half of recipients from death by restoring liver functions. Our study provides a novel strategy to generate functional hepatocyte-like cells for the purpose of liver engineering and regenerative medicine.
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We would like to thank X. Chen, J. Cen, L. Zhang and J. Yuan for technical support, and F. Tang and D. Li for comments. The laboratory of L.H. is funded by the National Science Foundation of China (91019014) and the Chinese Academy of Sciences (KSCX2-YW-R-241, XDA01010402 and the Hundred Talents Program). The laboratory of X.W. is supported by the National Science Foundation of China (30801115), Chinese National 863 Plan Project (2006AA02Z474) and National Key Basic Research and Development Program of China (2007CB947102 and 2009CB941100).
The authors declare no competing financial interests.
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Huang, P., He, Z., Ji, S. et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475, 386–389 (2011). https://doi.org/10.1038/nature10116
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