Stem cell warm-up via biomimetic mechanical priming enhances synovial-derived MSCs adaptation for meniscal repair

Objective: Mesenchymal stem cell (MSCs) transplantation shows promise for meniscus repair, but their inadaptability to the in vivo mechanical environment complicates differentiation regulation. This study developed a mechanical priming strategy to enhance MSCs fibrochondrogenic differentiation and promote meniscus repair. Methods: Synovial-derived MSCs (SMSCs) were co-cultured with meniscal fibrochondrocytes and exposed to cyclic tensile strain (10%, 0.5 Hz, 4h/day) for 5 days as a "stem cell warm-up system". Differentiation and mechanical adaptation were assessed through gene expression, cytoskeletal and nuclear morphology, and YAP-mediated mechanical transduction in vitro. A 2-mm meniscus defect model in New Zealand white rabbits was used, with histological analysis for repair evaluation. Results: Mechanical priming inhibited SMSCs hypertrophy and promoted fibrochondrogenesis, with effects lasting 72 h post-loading. Meanwhile, priming induced actin cap formation, nuclear flattening, and nuclear pore expansion, facilitating mechanical adaptation. YAP-mediated transduction was essential for the sustained upregulation of differentiation-related genes, alongside increased expression of its downstream targets, Ctgf and Cyr61. siRNA silencing of Ctgf and Cyr61 led to a downregulation of differentiation-related genes, with YAP inhibition further suppressing differentiation, underscoring its pivotal role in regulating this process. Primed SMSCs exhibited faster activation and better phenotype maintenance during secondary loading. In vivo, primed SMSCs demonstrated superior performance in meniscus regeneration, equivalent to the outcomes of growth factor-treated groups. Conclusions: This biomimetic priming system enhances MSC differentiation and mechanical adaptability, offering a clinically translatable strategy for meniscus repair and load-bearing tissue regeneration.