Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions.

Human embryonic stem cells (ESCs [hESCs]) proliferate as colonies wherein individual cells are strongly adhered to one another This architecture is linked to hESC self renewal, pluripotency, and survival and depends on epithelial cadherin (E cadherin), NMMIIA (nonmuscle myosin IIA), and p120-catenin E cadherin and p120-catenin work within a positive feedback loop that promotes localized accumulation of E cadherin at intercellular junctions NMMIIA stabilizes p120-catenin protein and controls E cadherin mediated intercellular adhesion Perturbations of this signaling network disrupt colony formation, destabilize the transcriptional regulatory circuitry for pluripotency, and impair long term survival of hESCs Furthermore, depletion of E-cadherin markedly reduces the efficiency of reprogramming of human somatic cells to an ESC like state The feedback regulation and mechanical biochemical integration pro vide mechanistic insights for the regulation of intercellular adhesion and cellular architecture in hESCs during long term self-renewal Our findings also contribute to the understanding of microenvironmental regulation of hESC identity and somatic reprogramming