p53 regulates pluripotency of embryonic stem cells via microenvironmental fibronectin-integrin interaction

Feeders make necessary contributions to maintaining pluripotency and have been widely used for culturing embryonic stem cells (ESCs). Here, we showed p53 in feeders is required for ESC self-renewal. Following ablation of p53 in feeders, ESCs attenuated their pluripotent characteristics, with hyperactivation of ERK. We established that p53 in feeders transcriptionally actives MMP-2 or -9, thereby promoting degradation of fibronectin, preventing its interaction with integrins in ESCs and subsequent activation of integrin/FAK/ERK pathway. Based on these, we developed a new 2i or 1i system for ESC culture. Moreover, treatment of human pluripotent stem cells, or tissue stem cells with a fibronectin-integrin inhibitor strongly increased Sox2 and Oct4 levels. Our findings demonstrate a cross-cell function for p53 in regulating pluripotency, reveal a novel feeder-action mechanism beneficial for developing new stem cell culture conditions.