Membrane Potential Depolarization Alters Calcium Flux and Phosphate Signaling During Osteogenic Differentiation of Human Mesenchymal Stem Cells

Background: Membrane potential (V mem ) changes accompany important events in embryonic development and organ regeneration. Recent studies have pointed to its function as a potent regulator of cell proliferation, differentiation, migration, and tissue regeneration. We have previously reported that V mem depolarization and hyperpolarization control the osteogenic (OS) differentiation potential of human mesenchymal stem cells (hMSCs). Materials and Methods: In this study, we sought to understand the mechanism(s) underlying voltage regulation of hMSC differentiation. We investigated the role of calcium and phosphate ion flux in the depolarization response of OS-differentiating hMSCs, as these ions are the two major inorganic components of the bone mineral matrix and are indicative of mature osteoblast function. Results: Our results suggest that inorganic phosphate levels play a larger role than calcium flux in mediating hMSC response to depolarization and that the expression of stanniocalcin 1 (STC1), a protein that regulates calcium and phosphate homeostasis in osteoblasts, is functionally required for the depolarization response during the early stages of differentiation. Conclusion: Depolarization alters hMSC differentiation through a phosphate signaling pathway involving STC1. This study enriches our mechanistic understanding of hMSC response to endogenous voltage cues.