Mechanotransduction in human islets of Langerhans : implications for β cell fate

Background and aim. The interaction between cells and the extracellular environment plays a pivotal role in tissue differentiation and fate, both in physiological and pathological conditions. Like other cells, β-cell behaviour is strongly influenced by extracellular matrix interactions which are organized at the nanoscale level, but the contribution of nanotopography on β-cell fate has never been explored. Aim of the proposed research was to investigate whether human β-cells can regulate their behaviour in response to nanoscale features and characterize the molecular mechanisms involved. Material and methods. Transition metal oxide nanostructured surfaces were fabricated as substrates to study the effects of nanoscale topography on β-cell behaviour. Human islets were grown on these substrates for 15 days and β-cell function and viability were assessed by measuring insulin secretion and apoptosis. The mechanotransductive signalling complexes were characterized by proteomic analysis and super-resolution imaging techniques. Results. β-cell survival and function were improved on nanostructured substrates as revealed by insulin secretion experiments and TUNEL assays. Proteomic analysis demonstrates that β-cells respond to the substrate nanotopography through the up-regulation of proteins involved in the integrin signalling and actin polymerization. Super-resolution imaging techniques and quantitative immunofluorescence analyses confirmed modifications in cell-substrate adhesion complexes and reorganization of the actin cytoskeleton. Conclusions. Our data reveal that β-cells respond to the microenvironment morphology by activating a mechanotransductive signalling pathway which greatly promotes their survival and function. Characterizing the mechanotransductive signalling involved at the molecular level may offer a unique opportunity for identifying potential therapeutic targets of intervention in diabetes mellitus.