A PTN-Rich MSC Subtype Promotes Cartilage Repair in End-Stage Knee Osteoarthritis

Mesenchymal stem cell (MSC) therapy for end-stage knee osteoarthritis (KOA) shows inconsistent efficacy, and whether MSCs retain cartilage repair capacity in the inflammatory joint remains unclear. Using single-cell RNA sequencing of human Kellgren-Lawrence grade Ⅲ (G Ⅲ) and Ⅳ (G Ⅳ) KOA joint tissues and exogenous MSCs, we found that pleiotrophin (PTN) signalling shifts from MSC-chondrocyte crosstalk to chondrocyte-dominated autocrine signalling, with PTN exhaustion and elevated cluster of differentiation 74 (CD74) in G Ⅳ cartilage. We therefore identified and sorted a PTN-rich CD74-low placenta-derived MSC subtype and evaluated it in a murine KOA model and in co-culture with patient-derived chondrocytes. This subtype enhanced cartilage repair, upregulated SOX9, and suppressed MMP13, CD74, IL-6, and IL-1β, potentially through CD74 suppression and reduced NF-κB signaling. These findings provide a basis for functionally defined, stage-matched cell therapy tailored to the pathological microenvironment of end-stage KOA.