Lineage-Specific Differentiation Is Influenced by State of Human Pluripotency

Publication date: 4 April 2017
Source:Cell Reports, Volume 19, Issue 1
Author(s): Jong-Hee Lee, Sarah Laronde, Tony J. Collins, Zoya Shapovalova, Borko Tanasijevic, Jamie D. McNicol, Aline Fiebig-Comyn, Yannick D. Benoit, Jung Bok Lee, Ryan R. Mitchell, Mickie Bhatia
Human pluripotent stem cells (hPSCs) have been reported in naive and primed states. However, the ability to generate mature cell types remains the imperative property for utility of hPSCs. Here, we reveal that the naive state enhances self-renewal while restricting lineage differentiation in vitro to neural default fate. Molecular analyses indicate expression of multiple lineage-associated transcripts in naive hPSCs that failed to predict biased functional differentiation capacity. Naive hPSCs can be converted to primed state over long-term serial passage that permits recovery of multi-germ layer differentiation. Suppression of OCT4 but not NANOG allows immediate recovery directly from naive state. To this end, we identified chemical inhibitors of OCT4 that restore naive hPSC differentiation. Our study reveals unique cell-fate restrictions in human pluripotent states and provides an approach to overcome these barriers that harness both efficient naive hPSC growth while maintaining in vitro differentiation essential for hPSC applications.

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Teaser

Lee et al. describe functional properties unique to human naive pluripotent stem cells that prevent generation of a full repertoire of differentiated cell types for in vitro study. This can be overcome through reduction of the pluripotency factor, OCT4, by genetic means or use of small molecules.


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