Effects of mechanotransduction on β-cell differentiation and function in human islets of Langerhans

Pancreatic β-cells are constantly exposed to mechanical stimuli arising from the surrounding extracellular matrix (ECM), but whether and how these stimuli contribute to β-cell differentiation and function is largely unknown. We used cluster-assembled zirconia substrates with tailored roughness to mimic the ECM nanotopography and stiffness and to evaluate the effects of mechanical forces on human islet of Langerhans survival and function. We found that human β-cells viability and function are improved on nanostructured substrates: β-cells contain several dispersed insulin granules and show increased glucose-stimulated calcium currents and insulin secretion. Quantitative immunofluorescence revealed the reorganization of focal adhesions, the actin cytoskeleton and the nuclear architecture. Proteomic analysis confirmed that β-cells respond to mechanical forces through the activation of different mechanosensors, including mechanosensitive ion channels and integrins (GO: 0005925). Their activation causes the remodeling of the actomyosin cytoskeleton (GO: 0005856) and nuclear architecture (GO: 0031891) and it is conveyed to the nucleus where it modulates gene expression. Characterizing the mechanotransductive pathway may offer a unique possibility to understand how β-cells work and can lead to the identification of new targets of pharmacological intervention in diabetes.