Exploiting mechanotransductive processes to promote pancreatic β-cell differentiation and function

Introduction. Pancreatic β-cells, by releasing insulin, play a critical role in the control of glucose homeostasis. In vivo, they reside in the islet niche, which provides a myriad of stimuli derived from the extracellular matrix (ECM) and the neighbouring cells. This multifaceted environment plays a pivotal role in the regulation of pancreas development and in the control of β-cell function. Even though the contribution of chemical stimuli has been widely investigated, the mechanical signals are poorly known. Therefore, the aim of the proposed research was to explore the role of nanotopography in the regulation of β-cell functionality and to investigate the underlying molecular mechanisms.

Methods. Human islets of Langerhans were grown on cluster-assembled zirconia substrates with a tailored roughness mimicking the ECM nanotopography, and flat zirconia substrates were used as controls. The β-cell functionality was evaluated by means of super-resolution fluorescence microscopy, Western blot, and ELISAs and confirmed by shot-gun proteomics.

Results. Quantitative immunofluorescence revealed that β-cells are mechanosensitive and respond to nanotopography through mechanotransduction, which impacts on focal adhesions and cytoskeletal and nuclear organization. These modifications are paralleled by a profound gene reprogramming which promotes the expression of pro-survival and pro-differentiation factors and proteins involved in the regulation of granule trafficking in the islets grown on the nanostructure. In line with these observations, we found that the nanotopography preserves β-cell differentiation and function in long-term cultured islets, as suggested by increased β-cell number, reduced β-cell death, and potentiated glucose-stimulated insulin secretion.

Conclusions. This study provides a better understanding of how mechanical forces contribute to β-cell fate, offering the possibility to harness these mechanisms for promoting β-cell function in physiological and pathological conditions.