The roles of mechanotransduction in pluripotency and cell fate decisions (360G-Wellcome-203800_Z_16_A)

Embryonic stem cells have the ability to differentiate into all somatic lineages of the embryo, a property known as pluripotency. The behaviour of pluripotent stem cells is regulated by multiple signals from the microenvironment. While the soluble biochemical cues involved in maintaining pluripotency have been studied extensively, the roles of mechanical forces are not well understood. I aim to use a novel polyacrylamide hydrogel (StemBond) with tuneable stiffness and adhesive properties to study how mechanical properties of the cells' environment, particularly substrate stiffness, affect pluripotency and cell fate decisions. This will allow tighter control over pluripotent stem cell maintenance in vitro, and importantly, differentiation into mature cell types that can be used for stem cell therapies and disease modelling. Specifically, I aim to identify the factors and pathways involved in the mechanical regulation of pluripotency maintenance and exit, and study how soluble and mechanical factors interact in response to changes in substrate stiffness. Additionally, I will probe the effects of substrate stiffness, and its synergy with soluble factors, in controlling lineage decisions. These insights will be used to achieve improved derivation of differentiated cell types, such as those of the pancreas, from human embryonic stem cells.