What happens with equine mesenchymal stem cells following in vivo allogeneic administration? Role of their interactions with the patient's immune system

Objectives:

Allogeneic therapy with equine mesenchymal stem cells (MSCs) presents advantages over autologous therapy, but immune recognition of foreign cells can compromise safety and effectiveness. Such recognition is related to the matching/mismatching for the major histocompatibility complex (MHC) between donor and patient, to MHC expression levels and MSC immunomodulatory properties, which can change after inflammatory exposure or differentiation.

Methods:

Three alginate scaffolds containing basal (MSC-naïve), pro-inflammatory primed (MSC-primed) or chondrogenically differentiated (MSC-chondro) MSCs were placed subcutaneously in 17 MHCmatched/ mismatched horses, and recovered at different time-points to analyse local immune reaction (histology) and gene expression (immunomodulatory/immunogenic genes). Procedure was repeated to assess the effect of a second administration.

Results:

Both MHC-matched/mismatched MSC-chondro exhibited the highest immunomodulatory profile with minimal local reaction, and their administration in MHC-mismatched horses did not increase their immunogenic profile. MSC-naïve administered to MHC-mismatched recipients showed a lower immunomodulatory profile and led to a higher local immune response compared to MHC-matched recipients. MSC-primed administration resulted in an earlier recruitment of lymphocytes, accompanied by a decrease in MSC expression of immunomodulation-related genes and an increase in immunogenic-related genes. However, MHC-matched recipients of MSC primed showed lower histiocyte reaction over MHC-mismatched ones.

Conclusions:

MSC-chondro may be more appropriate when donor and patient are MHC-mismatched, while MHC- matched donors would be recommended for MSC-naïve administration to minimize immune reactions. MSC-primed have been previously reported as more regulatory, but further research is needed to fully understand their interactions with host’s immune system in order to select MSCs for allogeneic therapy.