Immunomodulation in mesenchymal stem cell therapy for osteoarthritis: mechanistic insights on the role of cell death and engraftment
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Osteoarthritis (OA) is a degenerative pathology of the articular cartilage causing chronic pain and disability in millions of individuals. In OA synovia, resident macrophages and infiltrated lymphocytes contribute to the disease progression by releasing catabolic mediators that interfere with the reparative process. Mesenchymal stem cells (MSCs) possess the capacity to release immune-modulating cytokines when licensed by proinflammatory stimuli. They were also proven to promote regeneration in pre-clinical models of OA and to improve disease scores in small-scale clinical trials. To assess whether MSCs act by alleviating synovitis, a novel approach was optimised to retrieve GFP+ cells after intra-articular (IA) injection into a murine model of collagenaseinduced OA (CIOA). MSCs were separated from knee digests by FACS-coupled cell sorting and expanded in culture for further characterisation. Retrieval and processing did not affect their proliferation rates or clonogenicity but slightly altered their differentiative potential. CIOA-retrieved MSCs had no effect on syngeneic T cells in co-culture experiments. However, their conditioned medium (CM) caused polarisation of in vitro activated macrophages towards an M2 immunomodulatory phenotype, with lower expression of MHC-II and CD86 and increased secretion of IL-10. The immunomodulatory effect of CIOA-challenged MSCs was significant, compared to both naïve MSCs and MSCs injected in sham-treated animals. As only 1.627% of the implanted MSCs was successfully retrieved, it was postulated that MSCs act via a hit-and-run mechanism, with release of cytokines following rapid apoptosis. In vitro-induced apoptosis promoted a similar trophic-mediated M2 switch, resulting in significantly higher IL-10 secretion from macrophages. However, apoptotic MSCs also prevented proliferation and activation of co-cultured lymphocytes. The presented data demonstrates that, following IA administration, a large proportion of MSCs undergoes apoptosis and exert non-specific immunomodulatory effects. A smaller percentage acquire a licensed phenotype which aids in the resolution of synovitis through a paracrine mechanism indirectly mediated by reprogrammed macrophages.