miR-203 imposes an intrinsic barrier during cellular reprogramming by targeting NFATC2

Cellular reprogramming from somatic to pluripotent cells is the basis for multiple applications aimed to replace damaged tissues in regenerative medicine. However, this process is limited by intrinsic barriers that are induced in response to reprogramming factors. In this manuscript we report that miR-203, a microRNA with multiple functions in differentiation and tumor suppression, acts as an endogenous barrier to reprogramming. Genetic ablation of miR-203 results in enhanced reprogramming whereas its expression prevents the formation of pluripotent cells both in vitro and in vivo. Mechanistically, this effect correlates with the direct repression of NFATC2, a transcription factor involved in the early phases of reprogramming. Inhibition of NFATC2 mimics miR-203 effects whereas NFATC2 overexpression rescues inducible cell pluripotency in miR-203-overexpressing cultures. These data suggest that miR-203 repression may favor the efficiency of reprogramming in a variety of cellular models.