YAP–TEAD1 control of cytoskeleton dynamics and intracellular tension guides human pluripotent stem cell mesoderm specification

Abstract

The tight regulation of cytoskeleton dynamics is required for a number of cellular processes, including migration, division and differentiation. YAP–TEAD respond to cell–cell interaction and to substrate mechanics and, among their downstream effects, prompt focal adhesion (FA) gene transcription, thus contributing to FA-cytoskeleton stability. This activity is key to the definition of adult cell mechanical properties and function. Its regulation and role in pluripotent stem cells are poorly understood. Human PSCs display a sustained basal YAP-driven transcriptional activity despite they grow in very dense colonies, indicating these cells are insensitive to contact inhibition. PSC inability to perceive cell–cell interactions can be restored by tampering with Tankyrase enzyme, thus favouring AMOT inhibition of YAP function. YAP–TEAD complex is promptly inactivated when germ layers are specified, and this event is needed to adjust PSC mechanical properties in response to physiological substrate stiffness. By providing evidence that YAP–TEAD1 complex targets key genes encoding for proteins involved in cytoskeleton dynamics, we suggest that substrate mechanics can direct PSC specification by influencing cytoskeleton arrangement and intracellular tension. We propose an aberrant activation of YAP–TEAD1 axis alters PSC potency by inhibiting cytoskeleton dynamics, thus paralyzing the changes in shape requested for the acquisition of the given phenotype.

Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression

“…Mechanoregulation of YAP/TAZ plays a critical role in normal development and aging processes. For instance, it is known that physiological substrate stiffness directs human pluripotent stem cell specification by influencing cytoskeleton arrangement and intracellular tension through the YAP-TEAD complex ( Pagliari et al, 2021 ). The behavior of limbal epithelial stem cells is strongly influenced by changes in corneal substrate stiffness, via the activation of YAP-dependent mechanotransduction pathways ( Gouveia et al, 2019 ).…”

Mitochondrial dysfunction by TFAM depletion disrupts self-renewal and lineage differentiation of human PSCs by affecting cell proliferation and YAP response

“…In 2006, Engler and colleagues demonstrated that stem cells have different fate-determining tendencies in additional substrate stiffness [ 28 ]. The YAP-TEAD1 axis, regulated by ECM stiffening, could direct hPSCs specification by influencing cytoskeleton arrangement and intracellular tension [ 29 ], also appeared in our RNA-seq results. Then we tested the YAP-TEAD1 axis in our system and observed a significantly higher YAP nucleus-localized signal in TFAM-knockout cells ( Fig.…”

“…Previous studies showed that some cellular processes, including migration and differentiation, are related to cytoskeleton dynamics regulated by the YAP-TEAD signaling pathway. Also, a recent study characterized that the regulation of the YAP-TEAD axis in response to substrate rigidity directs hPSC mesoderm specification by controlling cytoskeleton dynamics [ 29 ]. Consistent with the above results, we show that TFAM promotes mesoderm formation via maintaining the YAP-TEAD pathway.…”

Trp53 and Rb1 deficiency in chondrocytes spontaneously develop chondrosarcoma by activation of YAP signaling

“…4E, F). To further examine YAP/TEAD1 transcriptional activity, we conducted 8xGTIIC-luciferase assay which was confirmed with high specificity and sensitivity [17,30,31]. The result showed a significantly increased transcriptional activity of YAP in Trp53/Rb1-deficient chondrocytes (Fig.…”