Mechanotransductive signaling pathway in human islets of Langerhans: implications for β-cell survival and function

Pancreatic β-cells are constantly exposed to mechanical stimuli arising from the surrounding extracellular matrix (ECM), neighboring cells and blood flow, but whether and how these stimuli contribute to β-cell differentiation and function is largely unknown. By exploiting cluster-assembled zirconia substrates with tailored roughness to mimic the nanotopography and stiffness of the ECM, we investigate the effect of mechanical forces on human islet of Langerhans survival and function. Human β-cells viability and function are improved on nanostructured substrates: β-cells contain several dispersed insulin granules and show increased glucose-sensitive calcium currents and insulin secretion. Quantitative immunofluorescence analysis reveals reorganization of the cell-substrate adhesion complexes, the actin cytoskeleton and the nuclear architecture. Proteomic analysis demonstrate protein changes that are congruent with the functional and morphological results and shows that β-cells respond to mechanical forces through the activation of a certain number of mechanosensors, including mechanosensitive ion channels and integrins (Gene Ontology GO terms: 0005925). Their activation causes remodeling of the actomyosin cytoskeleton (GO: 0005856) and nuclear architecture (GO: 0031891) and is conveyed to the nucleus where it modulates gene expression. The characterization of the mechanotransduction signaling pathway may offer a unique possibility to understand how beta cells work and can lead to the identification of new targets of pharmacological intervention in diabetes mellitus