FoxO3a Contributes to the Reprogramming Process and the Differentiation of Induced Pluripotent Stem Cells

Abstract

Induced pluripotent stem (iPS) cells, which are morphologically and functionally similar with embryonic stem (ES) cells, have been successfully generated from somatic cells through defined reprogramming transcription factors. Forkhead class O3a (FoxO3a) has been recently reported to play an important role in the homeostasis and maintenance of certain types of stem cells; however, the role of FoxO3a in the reprogramming process and differentiation of iPS cells remains unclear. In this study, we investigate the function of FoxO3a during the reprogramming process and characterize the properties of iPS cells from FoxO3a-wild type and -null mouse embryonic fibroblasts (MEFs). Our results show that the FoxO3a-null iPS cells are similar to the wild-type iPS cells in the levels of ES cell markers, alkaline phosphatase activity, and formation of teratoma in vivo. The reprogramming process is delayed in the FoxO3a-null MEFs compared to the wild-type MEFs; whereas the overexpression of FoxO3a partially recovers the impaired reprogramming efficiency in the null group. More importantly, FoxO3a deficiency impairs the neuronal lineage differentiation potential of iPS cells in vitro. These results suggest that FoxO3a affects the reprogramming kinetics and the neuronal lineage differentiation potential of the resulting iPS cells. Therefore, this study demonstrates a novel function of FoxO3a in cell reprogramming, which will help the development of alternative strategies for generating iPS cells.