Dichotomous role of Shp2 for naive and primed pluripotency maintenance in embryonic stem cells

Background The requirement of the Mek1 inhibitor (iMek1) during naive pluripotency maintenance results from the activation of the Mek1-Erk1/2 (Mek/Erk) signaling pathway upon leukemia inhibitory factor (LIF) stimulation. Methods Through a meta-analysis of previous genome-wide screening for negative regulators of naive pluripotency, Ptpn11 (encoding the Shp2 protein, which serves both as a tyrosine phosphatase and putative adapter), was predicted as one of the key factors for the negative modulation of naive pluripotency through LIF-dependent Jak/Stat3 signaling. Using an isogenic pair of naive and primed mouse embryonic stem cells (mESCs), we demonstrated the differential role of Shp2 in naive and primed pluripotency. Results Loss of Shp2 increased naive pluripotency by promoting Jak/Stat3 signaling and disturbed in vivo differentiation potential. In sharp contrast, Shp2 depletion significantly impeded the self-renewal of ESCs under primed culture conditions, which was concurrent with a reduction in Mek/Erk signaling. Similarly, upon treatment with an allosteric Shp2 inhibitor (iShp2), the cells sustained Stat3 phosphorylation and decoupled Mek/Erk signaling, thus iShp2 can replace the use of iMek1 for maintenance of naive ESCs. Conclusions Taken together, our findings highlight the differential roles of Shp2 in naive and primed pluripotency and propose the usage of iShp2 instead of iMek1 for the efficient maintenance and establishment of naive pluripotency.

Automated summary

This study discovered the differential roles of Shp2 in naive and primed pluripotency and proposed the usage of iShp2 instead of iMek1 for the efficient maintenance and establishment of naive pluripotency.