OBJECTIVES: Human periodontal ligament (PDL) progenitor cells (hPDLPCs) sense mechanical stress and differentiate into osteoblasts, cementoblasts, and fibroblasts during orthodontic tooth movement. The mechanosensitive ion channel Piezo1 has been known to be present in PDL tissues and is involved in mineralization during bone regeneration. However, the functional role and underlying mechanisms of Piezo1 in osteogenesis and cementogenesis are unknown. We hypothesize that Piezo proteins are expressed in and regulate the differentiation of hPDLPCs. METHODS: We examined the effects of Piezo1 activation, by agonist and mechanical stretching, on the expression of osteogenesis- and cementogenesis-related molecules in hPDLPCs using RT-PCR, western blotting, and immunofluorescence methods. RESULTS: hPDLPCs showed calcium influx in Piezo1 and Piezo2, but not in TRPV4 and its channels. In hPDLPCs, the Piezo1 agonist Yoda1 significantly upregulated osteogenesis- and cementogenesis-related molecules through the Ca CONCLUSIONS: hPDLPCs expressed Piezo1 and Piezo2. Yoda1, Piezo1 agonist, significantly upregulated osteogenesis- and cementogenesis-related molecules through the Ca