p53 safeguards chemical reprogramming of human somatic cells toward pluripotency

Cell fate manipulation is powerful for generating desired cell types through reprogramming. However, reprogramming induces dramatic changes in cell states and identities, which can be risky, necessitating strict regulation to ensure safety and efficiency. p53 is essential for genome stability; however, it functionally opposes oncogenes comprising the Yamanaka factors. Delicately balancing p53 activity for efficient reprogramming has proven challenging. Here, we demonstrate that p53 is essential for chemical reprogramming, unlike its inhibitory role in transcription factor-mediated reprogramming. Unexpectedly, suppressing p53 impairs the generation of chemically induced pluripotent stem cells (CiPSCs). p53 prevents excessive epithelial-to-mesenchymal transition during the early reprogramming stages. Retinoic acid signaling activation promotes CiPSC generation by leveraging p53's anti-metastatic function via BTG2. Cell proliferation ability is sustained in the presence of p53 expression by regulating p21 with chemicals. p53 preservation shows practical advantages in securing genome integrity; thus, chemical reprogramming is promising for delicately balancing p53 activity and achieving efficient reprogramming for cell fate manipulation.