Procr+ chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration.

Protein C receptor+ (Procr+) cells were identified as stem or progenitor cells in multiple adult tissues. However, whether mechanical stimuli fine-tune their activation and differentiation remain unknown. 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 stimulation by forced running significantly increased the frequency of Procr+ cells, whereas mechanical unloading by tail suspension showed opposite effects. Osteoarthritis (OA) activated Procr+ cells to repair cartilage erosion, whereas 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. In contrast, intra-articular administration of a Piezo1 agonist ameliorated OA symptoms. Purified mouse or human Procr+ superficial cells robustly repair articular cartilage after expansion and in vivo transplantation. Together, we discovered a mechanosensitive chondroprogenitor population indispensable for articular cartilage maintenance and regeneration.