Store-Operated Ca²⁺ Entry Contributes to Piezo1-Induced Ca²⁺ Increase in Human Endometrial Stem Cells

Endometrial mesenchymal stem cells (eMSCs) are a specific class of stromal cells which have the capability to migrate, develop and differentiate into different types of cells such as adipocytes, osteocytes or chondrocytes. It is this unique plasticity that makes the eMSCs significant for cellular therapy and regenerative medicine. Stem cells choose their way of development by analyzing the extracellular and intracellular signals generated by a mechanical force from the microenvironment. Mechanosensitive channels are part of the cellular toolkit that feels the mechanical environment and can transduce mechanical stimuli to intracellular signaling pathways. Here, we identify previously recorded, mechanosensitive (MS), stretch-activated channels as Piezo1 proteins in the plasma membrane of eMSCs. Piezo1 activity triggered by the channel agonist Yoda1 elicits influx of Ca²⁺, a known modulator of cytoskeleton reorganization and cell motility. We found that store-operated Ca²⁺ entry (SOCE) formed by Ca²⁺-selective channel ORAI1 and Ca²⁺ sensors STIM1/STIM2 contributes to Piezo1-induced Ca²⁺ influx in eMSCs. Particularly, the Yoda1-induced increase in intracellular Ca²⁺ ([Ca²⁺]_i) is partially abolished by 2-APB, a well-known inhibitor of SOCE. Flow cytometry analysis and wound healing assay showed that long-term activation of Piezo1 or SOCE does not have a cytotoxic effect on eMSCs but suppresses their migratory capacity and the rate of cell proliferation. We propose that the Piezo1 and SOCE are both important determinants in [Ca²⁺]_i regulation, which critically affects the migratory activity of eMSCs and, therefore, could influence the regenerative potential of these cells.