Mechanical Stimulation Modulates Extracellular Vesicle Secretion from Mesenchymal Stem Cells via Piezo1 and Hippo Pathway

Extracellular vesicles (EVs) play a crucial role in tissue regeneration regulation and have the potential to improve the clinical efficacy of mesenchymal stem cell (MSC) therapy. However, stabilizing and obtaining sufficient quantities of EVs remain a key limitation for their clinical translation. Previous studies have shown that using material hardness as a physical method to promote MSC paracrine secretion of EVs is theoretically feasible. By constructing cell culture environments of varying hardness, we found that a mechanically sensitive cation channel receptor, Piezo1, may play a key role in MSC perception of the external mechanical environment and the regulation of EV secretion. To verify this conclusion, we examined Piezo1 expression and MSC secretion of EVs in different mechanical culture environments, and tested the quantity and function of MSC paracrine secretion of EVs before and after Piezo1 activity/expression regulation. We also used high-throughput sequencing results and bioinformatics analysis to explore the specific steps involved in Piezo1's impact on EV production and the role of the Hippo pathway in this process. This study may elucidate the specific molecular mechanisms by which mechanical culture environment differences affect MSC paracrine secretion of EVs, and provide new theoretical support for the development of materials based on mechanical properties and the clinical translation of EV therapy.