Procr⁺ Chondroprogenitors Sense Mechanical Stimuli to Govern Articular Cartilage Maintenance and Regeneration

Protein C receptor (Procr) has been identified as an adult stem cell marker across multiple tissues. However, whether Procr labels mechanosensitive skeletal stem/progenitors remains elusive. Here, we found rare Procr+ cells in the superficial layer of tibial articular cartilage and meniscus, which keep replenishing chondrocytes in postnatal knee joints. Mechanical overload by forced running significantly increased the frequency of Procr+ cells, while mechanical unloading by tail suspension showed opposite effects. Post-traumatic osteoarthritis (OA) activated Procr+ cells to repair cartilage erosion, while genetic ablation of Procr+ cells accelerated OA progression. Pharmacological or genetic inhibition of the mechanosensor Piezo1 significantly blunted cartilage regeneration by Procr+ cells and exacerbated OA symptoms. In contrast, intra-articular administration of Piezo1 agonist showed therapeutic effects. Purified Procr+ cells efficiently repair articular cartilage defects after in vivo transplantation, which are conserved in humans. Taken together, we discovered a mechanosensitive chondroprogenitor population indispensable for articular cartilage maintenance and regeneration.