The differentiation ability of mesenchymal stem cells (MSCs) initially raised interest for treating musculoskeletal injuries in horses, but MSC paracrine activity has widened their scope for inflammatory and immune-mediated pathologies in both equine and human medicine. Furthermore, the similar etiopathogenesis of some diseases in both species has advanced the concept of “One Medicine, One Health”. This article reviews the current knowledge on the use of MSCs for equine pathologies beyond the locomotor system, highlighting the value of the horse as translational model. Ophthalmologic and reproductive disorders are among the most studied for MSC application. Equine asthma, equine metabolic syndrome, and endotoxemia have been less explored but offer an interesting scenario for human translation. The use of MSCs in wounds also provides a potential model for humans because of the healing particularities in both species. High-burden equine-specific pathologies such as laminitis have been suggested to benefit from MSC-therapy, and MSC application in challenging disorders such as neurologic conditions has been proposed. The available data are preliminary, however, and require further development to translate results into the clinic. Nevertheless, current evidence indicates a significant potential of equine MSCs to enlarge their range of application, with particular interest in pathologies analogous to human conditions.

Immunomodulation and immunogenicity are pivotal aspects for the therapeutic use of mesenchymal stem cells (MSCs). Since the horse is highly valuable as both a patient and translational model, further knowledge on equine MSC immune properties is required. This study analysed how inflammation, chondrogenic differentiation and compatibility for the major histocompatibility complex (MHC) influence the MSC immunomodulatory–immunogenicity balance. Equine MSCs in basal conditions, pro-inflammatory primed (MSC-primed) or chondrogenically differentiated (MSC-chondro) were co-cultured with either autologous or allogeneic MHC-matched/mismatched lymphocytes in immune-suppressive assays (immunomodulation) and in modified one-way mixed leukocyte reactions (immunogenicity). After co-culture, frequency and proliferation of T cell subsets and B cells were assessed by flow cytometry and interferon-ɣ (IFNɣ) secretion by ELISA. MSC-primed showed higher regulatory potential by decreasing proliferation of cytotoxic and helper T cells and B cells. However, MHC-mismatched MSC-primed can also activate lymphocytes (proliferative response and IFNɣ secretion), likely due to increased MHC-expression. MSC-chondro maintained their regulatory ability and did not increase their immunogenicity, but showed less capacity than MSC-primed to induce regulatory T cells and further stimulated B cells. Subsequent in vivo studies are needed to elucidate the complex interactions between MSCs and the recipient immune system, which is critical to develop safe and effective therapies.

Mesenchymal stem/stromal cells (MSCs) hold promise for treating different equine conditions but enter senescence during culture. Using induced pluripotent stem cells (iPSCs) to derive MSC-like cells (iMSCs) can increase cell availability and diminish the need for invasive and repeated tissue harvesting. While human iMSCs are intensively studied, research on equine iMSCs (eqiMSCs) is very limited and has focused on strategies for spontaneous differentiation to obtain these cells. The aim of this study was to obtain MSC-like cells from equine iPSCs (eqiPSCs) by directing their differentiation via the neural crest pathway. The resulting eqiMSCs downregulated pluripotent gene expression compared to originating eqiPSCs, and the majority of lines met most of the standard criteria for tissue-derived MSCs (immunophenotype and tri-lineage differentiation potential). Nevertheless, eqiMSCs showed some differences from primary equine MSCs, possibly due to their different developmental origin, and displayed certain inter-line variability, which might be related to the different kinetics of independent eqiPSC lines. This study demonstrates for the first time that equine MSC-like cells (eqiMSCs) can be derived from eqiPSCs by directing their differentiation through the neural crest pathway. This constitutes an important advancement towards more sustainable sources of therapeutic cells in veterinary medicine and warrants further exploration of the functional characteristics of these novel cells.