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.

Central European Institute of Technology Masaryk University CZ 62500 Brno Czech Republic

Competence Center for Mechanobiology in Regenerative Medicine INTERREG ATCZ133 CZ 62500 Brno Czech Republic

Czech Academy of Sciences Institute of Theoretical and Applied Mechanics 190 00 Prague 9 Czech Republic

Department of Biomaterials Science Institute of Dentistry University of Turku FI 20014 Turku Finland

Department of Development and Regeneration KU Leuven 3000 Leuven Belgium

Department of Life Sciences Cattinara University Hospital Trieste University 1 34149 Trieste Italy

Faculty of Medicine Department of Biology Masaryk University CZ 62500 Brno Czech Republic

Institute of Nanotechnology National Research Council c o Campus EcoTekne via Monteroni 73100 Lecce Italy

International Clinical Research Center of St Anne's University Hospital CZ 65691 Brno Czech Republic

Università Campus Bio Medico di Roma Rome Italy

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$a YAP-TEAD1 control of cytoskeleton dynamics and intracellular tension guides human pluripotent stem cell mesoderm specification / $c S. Pagliari, V. Vinarsky, F. Martino, AR. Perestrelo, J. Oliver De La Cruz, G. Caluori, J. Vrbsky, P. Mozetic, A. Pompeiano, A. Zancla, SG. Ranjani, P. Skladal, D. Kytyr, Z. Zdráhal, G. Grassi, M. Sampaolesi, A. Rainer, G. Forte

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$a 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.

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