Lineage specific differentiation is influenced by state of human pluripotency [human]

Human pluripotent stem cells (hPSCs) have been reported in nave and primed states. However, the ability of human PSCs to generate mature cell types is the only imperative property for translational utility. Here, we reveal that the nave state enhances self-renewal capacity while restricting lineage differentiation in vitro to neural default fate. Gene expression analyses indicate expression of multiple lineage associated transcripts in nave hPSCs and thus failed to predict biased functional differentiation. Nave hPSCs can be converted to primed allowing recovery of multilineage differentiation over long serial passage or immediately through suppression of OCT4 but not NANOG. To this end, we identified chemical inhibitors of OCT4 expression that acutely restore nave hPSC differentiation. Our study identifies unique cell fate features and critical restrictions in human pluripotent states, and provides an approach to overcome these barriers that harness both efficient nave hPSC growth whilst maintaining in vitro differentiation capacities essential for hPSC applications.

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Lee JH, Laronde S, Collins TJ, Shapovalova Z, Tanasijevic B, McNicol JD, Fiebig-Comyn A, Benoit YD, Lee JB, Mitchell RR, Bhatia M