Identification of a putative progenitor-like chondrocyte subpopulation in osteoarthritic human cartilage

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage breakdown and limited intrinsic repair capacity. Recent single-cell RNA sequencing (scRNA-seq) studies have revealed remarkable chondrocyte heterogeneity, identifying multiple functionally distinct subpopulations. Increasing evidence suggests that articular cartilage harbors progenitor-like chondrocytes with regenerative potential.

Articular chondrocytes were isolated from knee cartilage of six end-stage OA patients and profiled using droplet-based scRNA-seq (~ 14,000 cells). Unsupervised clustering, differential gene expression, and gene ontology (GO) enrichment analyses were performed to define subpopulations and their functional characteristics. Pseudotime trajectory analysis (Monocle) was used to infer lineage relationships and differentiation hierarchies.

Twelve transcriptionally distinct chondrocyte clusters were identified, including seven previously described subsets-proliferative, prehypertrophic, hypertrophic, fibrochondrocytic, effector, regulatory, and homeostatic chondrocytes-and three novel ones: NRF2⁺ regulatory chondrocytes enriched in antioxidant pathways, secretory chondrocytes, and progenitor-like chondrocytes(PLCs). Cluster 11 (PLCs) accounted for approximately 2-5% of total chondrocytes and exhibited high expression of stemness-associated genes such as RGS5, PDGFRB, THY1 (CD90), MCAM (CD146), TAGLN, SPARCL1, COL4A1, and ID3. Gene ontology (GO) enrichment revealed activation of developmental and extracellular matrix organization programs, suggesting that these cells are transcriptionally primed for tissue remodelling. Pseudotime mapping positioned PLCs at an early bifurcation upstream of differentiated chondrocyte states, consistent with their progenitor-like role.

This study delineates the single-cell transcriptomic landscape of OA cartilage and identifies a distinct progenitor-like chondrocyte (PLC) subpopulation with progenitor-associated gene signatures. While functional and spatial validation are still required, the unique molecular features of PLCs raise the hypothesis that they may participate in both intrinsic attempts at cartilage repair and osteoarthritis pathophysiology. These findings provide a conceptual and molecular framework for future studies aimed at isolating PLCs, defining their in vivo behaviour, and exploring their potential as targets for cartilage regeneration or OA modulation.