Integrin-Associated Focal Adhesion Kinase Protects Human Embryonic Stem Cells from Apoptosis, Detachment, and Differentiation

Abstract

SummaryHuman embryonic stem cells (hESCs) can be maintained in a fully defined niche on extracellular matrix substrates, to which they attach through integrin receptors. However, the underlying integrin signaling mechanisms, and their contribution to hESC behavior, are largely unknown. Here, we show that focal adhesion kinase (FAK) transduces integrin activation and supports hESC survival, substrate adhesion, and maintenance of the undifferentiated state. After inhibiting FAK kinase activity we show that hESCs undergo cell detachment-dependent apoptosis or differentiation. We also report deactivation of FAK downstream targets, AKT and MDM2, and upregulation of p53, all key players in hESC regulatory networks. Loss of integrin activity or FAK also induces cell aggregation, revealing a role in the cell-cell interactions of hESCs. This study provides insight into the integrin signaling cascade activated in hESCs and reveals in FAK a key player in the maintenance of hESC survival and undifferentiated state.

Integrins functioning in uterine endometrial stromal and epithelial cells in estrus

“…The ECM, a non-cellular 3D macromolecular network composed of diverse fibrous ECM proteins, proteoglycans and glycoproteins (Kim et al 2011, Theocharis et al 2016 provides not only a physical scaffold to structure the 3D microenvironment but also signals a variety of cellular responses (Strauss 2013, Leppert et al 2014. In particular, ECM-derived signals are transported to the cytoplasm through integrins that directly recognize components of the ECM (Rosso et al 2004, Byron & Frame 2016, resulting in cytological alterations (Gronthos et al 2001, Vitillo et al 2016. Therefore, the stimulation of ECM protein-derived signals through integrins makes it possible to accurately regulate the specificity of endometrial cells at each stage of the estrus cycle, which requires detailed information on the integrins that are functionally expressed on the membranes of cells that make up the endometrium.…”

Inhibition of Rho‑associated protein kinase improves the survival of human induced pluripotent stem cell‑derived cardiomyocytes after dissociation

“…Recently, Yan et al (36) demonstrated that the application of Y27632 promoted the gene expression of matrix metalloproteinases 2/3 and Notch-1 signaling to modulate Yes-associated protein-1 localization in the regulation of efficient patterning of cardiovascular spheroids following mesoderm formation from hPSC. Therefore, the possibility that ROCK kinase-associated integrin signaling and receptors may be associated with cardiomyocyte maturation, physiological function, proliferation and apoptosis, which has not been examined in depth in the present study, cannot be ruled out (37,38).…”

Endothelial Differentiation G Protein-Coupled Receptor 5 Plays an Important Role in Induction and Maintenance of Pluripotency

“…Another component of the hESCs cytoskeleton shown to be important for colony morphology is PAXILLIN . PAXILLIN is a multidomain protein that localizes primary to sites of cell adhesion to extracellular matrix, called FAs.…”