Integrin α10β1- selected mesenchymal stem cells are protective in a murine model of post-traumatic osteoarthritis

Abstract

BackgroundPost-traumatic osteoarthritis (PT-OA) is a debilitating condition with significant unmet clinical need. Mesenchymal stem cells (MSCs) represent promising candidates for the treatment of cartilage conditions, owing to their immunomodulatory and regenerative capacities. However, the marked heterogeneity of MSC preparations remains a major challenge for product standardization and prediction of therapeutic efficacy. We previously identified integrin 10{beta}1 as a marker for the selection of a more homogenous MSC preparation, with cartilage repair potential in vivo. In this study, we evaluated the therapeutic efficacy of human MSCs selected for high integrin 10{beta}1 expression in a murine PT-OA model, and compared their effects with those of unselected MSCs. MethodsUnselected or integrin 10-selected human bone marrow MSCs were characterized by flow cytometry and differentiation potential into adipogenic, osteogenic and chondrogenic lineages. Cells encapsulated into fibrin gel were applied intra-articularly at the time of surgery in the destabilization of the medial meniscus (DMM) mouse model of PT-OA. Eight weeks after DMM induction, severity of cartilage damage was assessed on Safranin O-stained sections using the OARSI scoring system. Synovitis, periarticular chondrogenesis, and osteophyte formation were evaluated histologically. OA-associated proteases, extracellular matrix degradation markers, and apoptosis were analyzed by immunohistochemistry, ELISA, and TUNEL assay. Persistence of transplanted human cells was assessed by PCR. ResultsIntegrin 10{beta}1-selected MSCs showed the characteristic MSCs immunophenotype and trilineage differentiation capacity. In vivo, treatment with integrin 10-selected MSCs significantly attenuated PT-OA-induced articular cartilage degeneration compared with both unselected MSCs and vehicle-treated controls. Further histopathological analyses revealed tendency toward reduced synovitis and periarticular chondrogenesis. Moreover, integrin 10-selected MSC treatment was associated with modest reductions in apoptotic activity and decreased expression of OA-related proteases and extracellular matrix degradation markers. Lastly, human cells were not detectable in joint tissues at the study endpoint. ConclusionsIntegrin 10-selected MSCs demonstrated superior chondroprotective effects compared with unselected MSCs, highlighting their potential as a standardized and efficacious cell therapy for PT-OA. These findings further validate the feasibility and safety of selection and in vivo administration of MSCs with high expression of integrin 10.