Promoting Pancreatic β-cell Differentiation and Function: The Influence of Nanotopography

Understanding how to control β-cell differentiation is of paramount importance in diabetes research. Pancreatic β-cells in vivo develop in a peculiar niche and are constantly exposed to chemical and physical cues arising from the surrounding extracellular matrix; while the effects of chemical stimuli have been widely characterized, poorly is known about the mechanical signals. By exploiting cluster-assembled zirconia substrates with tailored roughness to mimic the ECM nanotopography, we investigated its impact on β-cell fate. We found that the nanotopography preserve β-cell differentiation and function in long-term cultured islets. Proteomic analysis and quantitative immunofluorescence revealed that β-cells sense and respond to the nanotopography activating a mechanotransductive pathway which causes the remodeling of the cell-substrate adhesions, the reorganization of the actin cytoskeleton and the nuclear architecture, thus changing gene expression. We also provide evidence that the nanotopography evokes a mitomorphosis program, favoring mitochondrial networking and function. In conclusion, our data suggest that β-cells respond to nanoscale features by activating a mechanotransduction pathway which promotes their survival and function. Engineering microenvironment mirroring the biophysical properties of the islet niche may offer a unique strategy to elucidate how mechanical forces contribute to β-cell fate and to harness these mechanisms for promoting β-cell function.