Intra-articular xenogeneic mesenchymal stem cell-based therapy increases CD4⁺CD25⁺ cells in synovial fluid

Osteoarthritis (OA) is a chronic joint disease afflicting a substantial portion of the world's population with no currently available cure. Mesenchymal stem cell (MSC)-based therapies have been observed to have a mild beneficial effect in OA but the mechanism behind their action remains unclear. This study aimed to identify the lymphocytic response to a xenogeneic human umbilical cord-derived MSC-based cell therapy. A unilateral medial meniscal release model was employed in an ovine model of post-traumatic OA, with the contralateral limb employed as the control. A dose of 1.0 × 10⁷ MSCs was administered to a subset of the OA group as well as to a normal sham-operated group. Synovial fluid was aspirated periodically for 13 weeks for flow cytometry analysis. At the termination of the study the stifle joints were collected and analyzed for potential pathologic changes. Cell therapy induced a transient influx of CD4⁺ leukocytes; there was a similar significant increase in the proportion of CD4⁺CD25⁺ and CD4⁺CD25^hi leukocytes in response to cell therapy, the latter being a subset that may be composed of regulatory T cells. There was no significant effect of the cell therapy treatment on the proportion of synovial fluid-derived CD8⁺ cells or BAQ44A⁺ B cells. iNOS expression of intimal lining macrophages was evident but reduced in the cell therapy OA group suggesting macrophage phenotype transformation. There were no inflammatory or histological changes that could be attributed to the cell therapy. Cell therapy induced chemotaxis of CD4⁺ cells to the joint but these cells were not associated with pathological changes, despite their expression of activation markers (CD25⁺).