Focal Adhesion Mechanotransduction Regulates Stiffness-Directed Differentiation

Human mesenchymal stem cells (hMSCs) are capable of differentiating into mesodermal lineages, with their fate mirroring the tissue lineage possessing a matching in vivo stiffness. The precise mechanisms responsible for this mechanotransduction-induced change in fate are unknown beyond the requirement for force transmission from the extracellular niche through to the nucleus. As a result of cellular contraction, linker proteins connecting the cytoskeleton to the extracellular matrix (ECM) are exposed to differing levels of force and deform to different extents based on the adjacent ECM’s stiffness. Therefore, some of these linker proteins could act as ‘molecular strain gauges,’ as they have been shown to unfold in response to this force. The unfolding process could result in exposure of cryptic binding sites and induction of new signaling pathways. For example, talin exposes multiple vinculin binding sites under physiological force [1]. Vinculin binds at either end to talin and actin and is thought to change its conformation in conjunction with this force [2] similar to how a strain gauge works. Here we show that force-dependent changes in vinculin recruit MAPK1, inducing a signaling cascade that results in the expression of myogenic markers. Together these data suggest that specific proteins may act as ‘molecular strain gauges’ and play a role in mechanosensitive stem cell differentiation.