Identification and characterization of POSTN+ synovial progenitor cells in meniscus regeneration.

BACKGROUND: The meniscus exhibits a limited intrinsic self-repair capacity, particularly in its avascular inner region. A major obstacle in developing regenerative therapies is the lack of understanding at the cellular or molecular level regarding its repair and regeneration. This study aimed to characterize the critical cellular population that drives the meniscal healing process. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on human clinical meniscus samples and established a meniscal injury model in New Zealand white rabbits for parallel analysis. Computational analyses, including pseudotime trajectory inference, were conducted to delineate cellular states and transitions. To dynamically trace cell fate, lineage tracing was employed. Functional validation was achieved through the isolation, genetic manipulation, and transplantation of the candidate progenitor cells into injury models in vivo. RESULTS: scRNA-seq revealed that a population of synovium-derived fibroblasts, characterised by high periostin expression, represents a unique injury-responsive population. Upon meniscal injury, these cells proliferated and rapidly migrated to the lesion site. Both pseudotime analysis and lineage tracing confirmed that this population transitioned into a chondrogenic state during the later stages of meniscal healing, showing progenitor characteristics; hence, they were termed POSTN+ synovial progenitor cells (POSTN+ SPCs). Mechanistically, the transcription factor TCF7L1 was identified as a candidate regulator of their progenitor characteristics, and may involve Wnt/β-catenin signaling pathway. Transplantation of POSTN+ SPC-enriched cells enhanced meniscus healing in the animal model. CONCLUSION: This study identifies POSTN  +  SPCs as a candidate injury-responsive progenitor-like cell population that plays an important role in meniscus repair. These cells undergo dynamic activation, proliferation, and chondrogenic differentiation at the lesion site, providing a promising cellular target for functional meniscal regeneration. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our findings suggest that the recruitment or transplantation of POSTN + SPCs may hold promise as novel therapies to enhance functional meniscal regeneration.