N-cadherin crosstalk with integrin weakens the molecular clutch in response to surface viscosity

Abstract Mesenchymal stem cells (MSCs) interact with their surroundings via integrins, which link to the actin cytoskeleton and translate physical cues into biochemical signals via mechanotransduction. N-cadherins also link to the cytoskeleton and enable cell-cell communication. This crosstalk between integrins and cadherins modulate human MSC mechanotransduction and fate. Here, we explore the role of this crosstalk in the mechanosensing of viscosity using supported lipid bilayers as substrates of varying viscosity. We functionalize these lipid bilayers with an adhesion peptide from integrins (RGD) and from N-cadherins (HAVDI), and show that integrin- and cadherin-based adhesions compete, leading to an altered MSC mechanosensing response. This response is characterised by a viscosity-dependent increase in actin flow, and a decrease in adhesion size and YAP nuclear translocation when HAVDI ligation occurs. We model this competition via a modified molecular clutch model, which drives the integrin/cadherin crosstalk in response to surface viscosity, ultimately controlling MSC lineage commitment.