Transcription factor network in embryonic stem cells: heterogeneity under the stringency

Leukemia inhibitory factor (LIF) signaling regulates transcription factors to maintain the self-renewability and pluripotency of embryonic stem (ES) cells. Recently, we have proposed a network model that consists of transcription factors such as, Klf4, Sox2, Tbx3, Nanog, and Oct3/4, which form a parallel pathway downstream from LIF signaling (Nature, 460, 2009, Niwa et al.). In this parallel pathway, the transcription factors maintain the pluripotency of ES cells through mutual balance with some degree of redundancy and compensation. While self-renewability and pluripotency are maintained well under such seemingly stringent regulation, studies of single cells revealed heterogeneity among individual ES cells. This heterogeneity may underlie the mechanism that allows ES cells to exit self-renewal and enter into differentiation to exert pluripotency. Here we focus on recent studies on the heterogeneity of ES cells and discuss their inherent metastability.