A commonly used treatment for late stage/terminal liver diseases is liver transplantation. However, many patients die while waiting in line for liver donors. Therefore, the generation of functional hepatocytes independent of donor liver organs is of great therapeutic value for liver disease treatment. Induced hepatic differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells. 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, including neurons, cardiomyocytes and blood progenitors. However, it remains unclear whether these lineage-converted cells could repair damaged tissues in vivo. Here HUANG Pengyu and colleagues in Dr. HUI Lijian's lab, at the Institute of Biochemistry and Cell Biology (IBCB), Shanghai Institutes for Biological Sciences, CAS, provide a novel strategy to directly convert mouse fibroblasts to functional hepatocyte-like (iHep) cells.
In this new study, HUANG et al. isolated adult tail-tip fibroblast cells from mice deficient in the proliferation inhibitor gene, p19Arf, and expressed 14 transcription factors important for liver function. The resulting cells adopted an epithelial morphology and began expressing many markers of the hepatic lineage. Through a narrowing-down approach, a combination of just three genes was shown to be sufficient to induce a hepatocyte-like fate when p19Arf was inactivated. These induced hepatocyte-like cells, or iHep cells, shared many functions and gene expression patterns with primary hepatocytes. These iHep cells were tested for their ability to restore liver function by using the Fah-/- mouse line which lacks an enzyme key for tyrosine metabolism. With a drug in their water supply, these animals function normally, but when the drug is withdrawn, they experience liver failure and death within weeks. Transplantation of iHep cells into livers significantly extended the life of these mice and cell staining post-mortem indicated that iHep cells became repopulating the liver. Though iHep cells are not the same as primary hepatocytes, this study demonstrates that induced cells could have powerful therapeutic potential if these findings can be extended from the mouse to human.
This work entitled “Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors” was published online in Nature on May 11th, 2011.
This study was supported by the grants from the Chinese Academy of Sciences, The Ministry of Science and Technology, National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality. （IBCB）
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai, China
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Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors
a, Experimental design of iHep cell induction.
b, c, Morphology of mouse fibroblasts (b) and iHep cells (c).
d, e, Fah-/-, Rag2-/- mouse livers without (d) or with iHep cell transplantation (e).
(Image provided by Dr. HUI Lijian)