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Abstract
Improved fundamental understanding of how cells interpret microenvironmental signals
is integral to designing better biomaterial therapies. YAP/TAZ are key mediators of
mechanosensitive signaling; however, it is not clear how they are regulated by the
complex interplay of microenvironmental factors (e.g., stiffness and degradability)
and culture dimensionality. Using covalently crosslinked norbornene-functionalized
hyaluronic acid (HA) hydrogels with controlled stiffness (via crosslink density) and
degradability (via susceptibility of crosslinks to proteolysis), we found that human
mesenchymal stem cells (MSCs) displayed increased spreading and YAP/TAZ nuclear localization
when cultured atop stiffer hydrogels; however, the opposite trend was observed when
MSCs were encapsulated within degradable hydrogels. When stiffness-matched hydrogels
of reduced degradability were used, YAP/TAZ nuclear translocation was greater in cells
that were able to spread, which was confirmed through pharmacological inhibition of
YAP/TAZ and actin polymerization. Together, these data illustrate that YAP/TAZ signaling
is responsive to hydrogel stiffness and degradability, but the outcome is dependent
on the dimensionality of cell-biomaterial interactions.