PIEZO1 Is a Contextual Mechanosensor and Its Depletion in Scx‐Lineage Cells Accelerates Structural and Functional Recovery

ABSTRACT Previous work has identified PIEZO1 as an important mechanosensor in homeostatic tendon, where it detects mechanical overload and regulates tissue adaptation. Here, we investigated the consequences of PIEZO1 depletion during tendon healing using a full‐thickness central‐third patellar tendon defect model. Unexpectedly, mechanical testing revealed accelerated functional recovery in mice with ScxCre‐driven Piezo1 conditional knockout. Transmission electron microscopy and histological analyses further demonstrated accelerated structural recovery in ScxCre;Piezo1 f/f tendons. Bulk tissue transcriptomic analysis revealed overlapping core healing programs between mutant and wild‐type defect tendons, despite broader transcriptional remodeling in ScxCre;Piezo1 f/f tendons. However, ScxCre;Piezo1 f/f tendons showed a marked reduction in Scx + cells within the defect region, consistent with prior reports suggesting that this subpopulation can adversely affect tendon healing. In vitro assays indicated that the reduced accumulation of Scx + fibroblasts after Piezo1 conditional knockout may be attributed to impaired migration rather than reduced proliferation. Together, these findings reveal a context‐dependent role for PIEZO1 in tendon biology: while PIEZO1 supports mechanosensing and adaptation in mature tendon, it enables wound‐site recruitment of Scx + fibroblast populations that impair healing after injury.