Piezo1 balances the osteogenic-tenogenic plasticity of periosteal progenitor cells through the YAP pathway

The extremity tendons and bones are derived from limb bud mesenchyme, which eventually becomes cells of different tissues. Despite their common origin, it was widely believed that tenocytes and skeletal cells are distinct lineages without interconversion. However, we found that periosteal skeletal progenitor cells could transform between osteogenic and tenogenic commitment. SCX can label the periosteal progenitor cell population. Loss of Piezo1 arrests the periosteal progenitor cells in a progenitor state. Piezo1 deficiency leads to upregulation of Scx expression due to the inhibited YAP nuclear localization. Loss of Piezo1 showed increased tenogenic marker genes and decreased osteogenic marker genes. The periosteal progenitor cells can regenerate the injured tendon more robustly when Piezo1 is absent. Taken together, our data reveal that periosteal SCX⁺ progenitor cells compromise the osteogenic ability and acquire the tenocyte-biased lineage commitment after loss of Piezo1, providing a strategy to modulate the periosteal progenitor cells for tissue regeneration.