Abstract
Osteoarthritis (OA) is a painful, debilitating disease with no cure or treatments that can predictably stop/reverse its progression. Treatment is particularly difficult since articular cartilage lacks intrinsic repair capacity, despite mesenchymal stem cells (MSCs) being present in the joint with robust chondrogenic potential. While heterogeneity exists among MSC subtypes within human synovium, it remains unclear which populations can regenerate cartilage or impact OA progression. We clonally isolated MSCs from normal and OA patient synovium using indexed flow cytometry, then characterized them through differentiation assays and quantitative proteomics. MSC clones were transplanted into a xenograft rat OA model and evaluated by histology and immunofluorescence. We identified heterogeneity in putative MSCs within and between patient groups and their repair capacity in the rat model. However, traditional cell surface markers could not distinguish these subtypes, highlighting the need for single-cell level understanding. Using unbiased proteomics, we identified CD47 as a novel MSC marker. CD47(Hi) cells demonstrated robust treatment efficacy in the rat OA model and directly contributed to new articular cartilage formation. Characterizing MSC subtypes is essential for identifying candidates appropriate for clinical investigation and exploiting functional MSCs for cartilage regeneration strategies.