Finetuning ERK activity enables most somatic cells to reprogram into pluripotency

Abstract

AbstractSomatic cell reprogramming is a stochastic process typically resulting in only a small fraction of cells successfully converting into induced pluripotent stem cells (iPSCs). The molecular and cellular basis underlying this stochasticity remains elusive. Here we demonstrate that this stochasticity can be largely eliminated when extracellular signal-regulated kinase (ERK) activity is tuned within a narrow range by using the MEK inhibitor at one tenth the concentration in the 2i media. Without pharmacologic inhibition, cells tune ERK activity by TFII-IΔ, a multifunctional transcription factor that binds to and mediates ERK’s nuclear activation. We find TFII-IΔ to be an actin-binding protein. ERK activity is partially inhibited as TFII-IΔ binds to actin which accumulates inside the nucleus of cells undergoing morphological remodeling. Manipulating actin’s ability to accumulate inside the nucleus alters reprogramming amenability as well cell height. Actin-TFII-IΔ drive cell height to go above the minimal height required for pluripotency (10 μm). This work uncovers a mechanistic couple between cell morphology and identity, providing convenient practices to massively increase reprogramming efficiency.