<b><i>Piezo1</i></b><b> balances the osteogenic-tenogenic plasticity of periosteal progenitor cells through the YAP pathway</b>

In the early stages of musculoskeletal development, the extremity tendons and bones are derived from limb bud mesenchyme, which eventually become cells of different tissues. Despite this common origin, it was widely believed that tenocytes comprising the tendon and skeletal cells are distinct lineages without interconversion. However, we found that periosteal skeletal progenitor cells could transform between osteogenic and tenogenic commitment. Firstly, we found that the reduction of the cortical thickness in the Prx1 Cre; Piezo1 fl/fl mice is more severe than that in Ocn Cre; Piezo1 fl/fl mice. ScRNA-seq analysis of Prx1+ cells isolated from the periosteum of Prx1 Cre; Ai9/+<i> </i>mice and Prx1 Cre; Piezo1<i> </i>fl/fl; Ai9/+<i> </i>mice, reveals that loss of Piezo1 arrests the periosteal progenitor cells in a progenitor state. Further analysis shows that SCX can label the periosteal progenitor cell population. Piezo1 deficiency leads to upregulation of<i> Scx</i> expression due to the inhibited YAP nuclear localization in periosteal progenitor cells. Loss of <i>Piezo1</i> showed increased tenogenic marker genes and decreased osteogenic marker genes. Furthermore, 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.