The immunomodulation-immunogenicity balance of equine Mesenchymal Stem Cells (MSCs) is differentially affected by the immune cell response depending on inflammatory licensing and major histocompatibility complex (MHC) compatibility.
Authors: Cequier Alina, Vázquez Francisco José, Romero Antonio, Vitoria Arantza, Bernad Elvira, García-Martínez Mirta, Gascón Isabel, Barrachina Laura, Rodellar Clementina
Journal: Frontiers in veterinary science
Summary
# Editorial Summary Equine mesenchymal stem cells (MSCs) are increasingly used therapeutically for their immunomodulatory properties, but their behaviour when exposed to the recipient's immune system remains poorly understood—particularly in relation to donor-recipient MHC compatibility and inflammatory conditioning. Cequier and colleagues investigated how naive and pro-inflammatory cytokine-primed MSCs respond when co-cultured with autologous or allogeneic lymphocytes (matched or mismatched at the MHC locus), using gene expression and cytokine secretion as markers of immunomodulatory versus immunogenic profiles. Activated lymphocytes significantly amplified the immunosuppressive phenotype of primed MSCs, increasing IL-6, COX-2, and iNOS expression; however, the most striking finding was that primed MSCs exposed to MHC-mismatched (allogeneic) lymphocytes demonstrated the highest expression and secretion of these regulatory mediators, suggesting the immune challenge paradoxically enhanced their therapeutic potential rather than triggering rejection. Conversely, both MHC-matched and mismatched conditions upregulated MHC and immunogenic markers (including CD40) on primed MSCs when exposed to any lymphocyte population, indicating that allogeneic transplantation activates dual—potentially competing—immune profiles. Whilst these findings suggest that allogeneic MSC grafts may possess intrinsic mechanisms to intensify immunosuppression in response to immune recognition, translating this laboratory observation into clinical benefit requires in vivo validation before practitioners can confidently predict the longevity and efficacy of allogeneic versus autologous MSC therapies in horses.
Read the full abstract on PubMed
Practical Takeaways
- •Allogeneic MSC therapies may benefit from pre-priming with pro-inflammatory cytokines to enhance immunomodulatory capacity and reduce rejection risk
- •MHC matching may be less critical than previously thought for MSC efficacy, as mismatched cells may actually enhance their immune-evasive properties in inflammatory environments
- •Horses receiving MSC injections in acutely inflamed tissues may experience better therapeutic outcomes due to enhanced immunomodulatory signaling from activated lymphocytes
Key Findings
- •Cytokine priming and activated lymphocyte exposure synergistically upregulate immunomodulatory molecules (IL-6, COX-2, iNOS) in equine MSCs
- •MHC-mismatched MSC-primed cells exposed to activated lymphocytes showed highest expression of immunomodulatory mediators, suggesting enhanced immune evasion potential
- •Activated lymphocytes induce regulatory profiles in naive MSCs comparable to cytokine priming alone
- •MSC-primed cells upregulate MHC-I and MHC-II expression regardless of MHC compatibility when exposed to lymphocytes