MHC compatibility influences the interaction between different types of equine mesenchymal stem/stromal cells and the local immune response

The allogeneic administration of equine mesenchymal stem/stromal cells (MSCs) has numerous advantages over autologous therapy, but their interactions with the patient's immune system need to be further elucidated. These interactions can be influenced by factors such as the compatibility between donor-receptor for the major histocompatibility complex (MHC) and by the MHC expression levels, which can change under different conditions like inflammatory exposure and chondrogeneic differentiation. In this study, we evaluated the local immune response induced by chondrogeneically differentiated (MSC-chondro), pro-inflammatory primed (MSC-primed) and basal (MSC-naïve) MSCs, and how this response changes the immunomodulatory and immunogenic profiles of MSCs in vivo. Equine MSCs were embedded in alginate scaffolds and subcutaneously implanted into autologous, MHC-matched and MHC-mismatched horses. Scaffolds were recovered at different time-points for histologic and gene expression analyses, and the procedure was repeated to assess the effect of a second administration. Our results suggest that MHC-compatibility may play a key role in attenuating the local immune response induced by MSCs, which may be related to the upregulation of immunomodulatory genes in the three MSC types in vivo. In contrast, when MSCs were administered into MHC-mismatched horses, expression of immunogenic genes was higher across all MSC conditions. Therefore, the conditions in which MSCs are administered may not affect the long-term local immune response, but MHC-matched administration would favour the immune evasion of MSCs, thus being advisable especially when repeated MSC administrations are required. Comprehensively investigating the in vivo immune response against equine allogeneic MSCs is crucial for advancing veterinary cell therapies.