Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors

• Published in: Nature (London) Vol. 475; no. 7356; pp. 386 - 389
• Main Authors: Huang, Pengyu, He, Zhiying, Ji, Shuyi, Sun, Huawang, Xiang, Dao, Liu, Changcheng, Hu, Yiping, Wang, Xin, Hui, Lijian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.07.2011; Nature Publishing Group
• Subjects: 631/61/490; 692/698/2741/288/2032; 692/700/565/545/576; Animal cells; Animals; Biological and medical sciences; Biotechnology; Cell adhesion & migration; Cell Differentiation - genetics; Cell Lineage; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p16 - deficiency; Cyclin-Dependent Kinase Inhibitor p16 - genetics; DNA-Binding Proteins - deficiency; Embryonic stem cells; Eukaryotic cell cultures; Fibroblasts; Fibroblasts - cytology; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; GATA4 Transcription Factor - genetics; GATA4 Transcription Factor - metabolism; Gene expression; Gene Expression Profiling; Genetical aspects; Health aspects; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Hepatocyte Nuclear Factor 3-gamma - genetics; Hepatocyte Nuclear Factor 3-gamma - metabolism; Hepatocytes - cytology; Hepatocytes - metabolism; Hepatocytes - physiology; Hepatocytes - transplantation; Humanities and Social Sciences; Hydrolases - deficiency; Hydrolases - genetics; Inactivation; letter; Liver; Liver - cytology; Liver - enzymology; Liver - physiology; Liver - physiopathology; Liver cells; Liver Diseases - enzymology; Liver Diseases - pathology; Liver Diseases - physiopathology; Liver Diseases - therapy; Methods. Procedures. Technologies; Mice; Mice, Inbred NOD; Mice, SCID; multidisciplinary; Physiological aspects; Proteins; Regenerative Medicine - methods; Science; Science (multidisciplinary); Stem cells; Survival Rate; Tail - cytology; Tissue engineering; Tissue Engineering - methods; Transcription factors; Transduction, Genetic; United States; Cell culture; Vertebrata; Mammalia; Cell function; Hepatocyte; Mouse; Tissue engineering; Animal; Rodentia; Transcription factor; Fibroblast
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10116

Direct routes to liver-like cells Two groups report new approaches that could lead to the generation of hepatocyte-like cells for liver engineering and regenerative medicine. Lijian Hui and colleagues use a combination of Gata4, Hnf1a and Foxa3 overexpression and p19Arf inactivation to convert mouse fibroblasts directly into induced hepatic (iHep) cells that have gene-expression profiles close to that of mature hepatocytes. Sayaka Sekiya and Atsushi Suzuki identify three combinations of two transcription factors, comprising Hnf4a plus Foxa1, Foxa2 or Foxa3, that can convert mouse embryonic and adult fibroblasts directly into functional iHep cells. Both groups show that when iHep cells are transplanted into mice with a gene deficiency that models liver injury, the cells are able to repopulate the livers and restore their function. 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 disease 1 . Induced hepatic differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells 2 , 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 lineages 9 , 10 , 11 , 12 , including neurons 13 , cardiomyocytes 14 and blood progenitors 15 ; 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 p19 Arf . 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.