Induction of functional hepatocyte-like cells from mouse fibroblasts by
defined factors
Nature (2011) doi:10.1038/nature10116
Received 23 August 2010 Accepted 15 April 2011 Published online 11 May 2011
Affiliations
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell
Biology, Shanghai Institutes for
Biological Sciences, Chinese Academy for Sciences, Yueyang Road 320, 200031
Shanghai, China
Pengyu Huang, Zhiying He, Shuyi Ji, Huawang Sun, Changcheng Liu, Xin Wang &
Lijian Hui
Abstract:
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.
