Résumé : Embryonic stem cells (ESCs) cultured in vitro are functionally equivalent to the pluripotent stem cells of the early pre-implantation embryo. These cells have the potential to differentiate into all embryonic germ layers. The differentiation of ESCs is triggered by the removal of specific kinase inhibitors, which leads to the destabilization of the naïve pluripotency gene network, and the priming of lineage specification genes. The transition from naïve to primed state is characterized by striking morphological changes as cells go from tight round colonies to being flatter and spread out. They also appear to be increasingly sensitive to mechanical forces, as evidenced by the compliance and auxeticity of transition ESC nuclei (Pagliara et al., Nat. Mat., 2014). The actin cytoskeleton is known to have a significant role in determining cell morphology, adhesion strength and mechanosensitivity, yet how these properties are connected to ESC fate determination is unknown. We have developed several systems to test how external mechanical constraints impact cytoskeleton organization in ESCs, nuclear structure and ultimately regulate the exit of pluripotency. We first use compliant substrates with controlled adhesive density to study the crosstalk between mechanical signals and biochemical signaling pathways in naïve ESCs. Preliminary results show that compliant substrates enhance self-renewal of ESCs, through regulation of MAPK pathway. We also are developing a colony compression system to investigate how anisotropic stresses may drive different cell fates in colonies exiting pluripotency.
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