p53 safeguards chemical reprogramming of human somatic cells towards pluripotency [scRNA-seq]

Cell fate manipulation is powerful for generating desired cell types through reprogramming, such as induced pluripotent stem cells (iPSCs), with broad biological applications. However, reprogramming can be risky due to dramatic changes in cell identity, necessitating strict regulation to ensure safety and efficacy. p53 is essential for maintaining genome stability to prevent abnormalities induced by changes of cell states, which however, functionally counters Yamanaka factors for efficient reprogramming. Thus, delicately balancing p53 activity for efficient reprogramming with highly quality has proven challenging. Here, we demonstrate that efficient human chemical reprogramming is safeguarded by p53, in distinction from Yamanaka factors-mediated reprogramming. Suppressing p53 activity unexpectedly and substantially hinders the generation of chemically induced pluripotent stem cells (CiPSCs). Notably, p53 precisely regulates the mesenchymalization occurred at the early reprogramming stage where cell plasticity is re-established and curbs excessive epithelial-mesenchymal transition (EMT). Furthermore, the retinoid acid receptor agonist, TTNPB, leverages p53’s anti-metastatic functions to facilitate CiPSC generation by activating BTG2. Our results demonstrate that p53 activity distinguishes chemical reprogramming from Yamanaka factors-mediated reprogramming, and offer a promising strategy that delicately balances p53 with reprogramming for both safe and efficient cell fate manipulation.