Efficient derivation of functional hepatocytes from mouse induced pluripotent stem cells by a combination of cytokines and sodium butyrate

Qi Zhang, Yang Yang, Jian Zhang, Guo-Ying Wang, Wei Liu, Dong-Bo Qiu, Zi-Qing Hei, Qi-Long Ying, Gui-Hua Chen
Chinese Medical Journal 2011, 124 (22): 3786-93

BACKGROUND: Hepatocyte transplantation has been proposed as an alternative to whole-organ transplantation to support many forms of hepatic insufficiency. Unfortunately, the lack of donor livers makes it difficult to obtain enough viable human hepatocytes for hepatocyte-based therapies. Therefore, it is urgent to find new ways to provide ample hepatocytes. Induced pluripotent stem (iPS) cells, a breakthrough in stem cell research, may terminate these hinders for cell transplantation. For the promise of iPS cells to be realized in liver diseases, it is necessary to determine if and how efficient they can be differentiated into functional hepatocytes.

METHODS: In this study, we directly compared the hepatic-differentiation capacity of mouse iPS cells and embryonic stem (ES) cells with three different induction approaches: conditions via embryonic body (EB) formation plus cytokines, conditions by combination of dimethyl sulfoxide and sodium butyrate and chemically defined, serum free monolayer conditions. Among these three induction conditions, more homogenous populations can be promoted under chemically defined, serum free conditions. The cells generated under these conditions exhibited hepatic functions in vitro, including glycogen storage, indocynine green (ICG) uptake and release as well as urea secretion. Although efficient hepatocytes differentiation from mouse iPS cells were observed, mouse iPS cells showed relatively lower hepatic induction efficiency compared with mouse ES cells.

RESULTS: Mouse iPS cells would be efficiently differentiated into functional hepatocytes in vitro, which may be helpful in facilitating the development of hepatocytes for transplantation and for research on drug discovery.

CONCLUSION: We demonstrate that mouse iPS cells retain full potential for fetal liver development and describe procedures that facilitates the efficient generation of highly differentiated human hepatocyte-like cells from iPS cells in vitro.

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