Frequent and Transient Acquisition of Pluripotency During Somatic Cell Trans-Differentiation with iPSC Reprogramming Factors

Recent reports have proposed a new paradigm for obtaining mature somatic cell types from fibroblasts without going through a pluripotent state, by briefly expressing canonical iPSC reprogramming factors Oct4 , Sox2 , Klf4 , c-Myc (abbreviated as OSKM) in cells expanded in lineage differentiation promoting conditions. Here we apply genetic lineage tracing for endogenous Nanog locus and X chromosome reactivation during OSKM induced trans-differentiation, as these molecular events mark final stages for acquisition of induced pluripotency. Remarkably, the majority of reprogrammed cardiomyocytes or neural stem cells derived from mouse fibroblasts via OSKM mediated trans-differentiation (∼>90%), are attained after transient acquisition of pluripotency, and followed by rapid differentiation. Our findings underscore a molecular and functional coupling between inducing pluripotency and obtaining “trans-differentiated” somatic cells via OSKM induction, and have implications on defining molecular trajectories assumed during different cell reprogramming methods.