Nanog induced intermediate state in regulating stem cell differentiation and reprogramming

Background: Heterogeneous gene expressions of cells are widely observed in self-renewing pluripotent stem cells, suggesting possible coexistence of multiple cellular states with distinct characteristics. Though the elements regulating cellular states have been identified, the underlying dynamic mechanisms and the significance of such cellular heterogeneity remain elusive. Results: We present a gene regulatory network model to investigate the bimodal Nanog distribution in stem cells. Our model reveals a novel role of dynamic conversion between the cellular states of high and low Nanog levels. Model simulations demonstrate that the low-Nanog state benefits cell differentiation through serving as an intermediate state to reduce the barrier of transition. Interestingly, the existence of low-Nanog state dynamically slows down the reprogramming process, and additional Nanog activation is found to be essential to quickly attaining the fully reprogrammed cell state. Conclusions: Nanog has been recognized as a critical pluripotency gene in stem cell regulation. Our modeling results quantitatively show a dual role of Nanog during stem cell differentiation and reprogramming, and the importance of the intermediate state during cell state transitions. Our approach offers a general method for analyzing key regulatory factors controlling cell differentiation and reprogramming.