Investigating the immunomodulatory properties of human embryonic stem cell-derived mesenchymal stem cells

Abstract

The immunosuppressive property of mesenchymal stem cells (MSC) has been utilised to ameliorate autoimmune reactions such as graft-versus-host disease. However, variation exists in primary MSC isolated due to differences in donor age and tissue of origin. Alternatively, human embryonic stem cells (hESC) can be differentiated to homogeneous populations of MSC (hESCMSC), thus providing an unlimited source of MSC for cell therapy. In this study, the immunomodulatory properties of two hESC-MSC lines, hESC-MSC1 and hESC-MSC2, were compared with adult bone marrow-derived MSC (BM-MSC) and neonatal foreskin fibroblast (Fb). hESC-MSC were able to suppress the proliferation of anti-CD3/CD28-stimulated CD4+ T cells in contact and transwell systems. The immunosuppression was demonstrated by both the carboxyfluorescein diacetate succinimidyl ester (CFSE) and [3H]- thymidine proliferation assays. However, hESC-MSC were less potent and twice the number of adherent hESC-MSC (as measured by IC50) compared to BM-MSC and Fb were required to suppress T cell proliferation by 50%. Supernatants collected from transwells of MSC or Fb with T cells were shown to suppress T cell proliferation, suggesting that suppressive factors were only produced in the presence of activated T cells. Among several candidates, endothelial monocyte-activating polypeptide-II (EMAP-II) was identified as a potential suppressive factor. T cells also induced indoleamine-2,3- dioxygenase (IDO) expression in MSC and Fb. IDO led to the depletion of tryptophan, an essential amino acid, and/or the production of tryptophan metabolites (kynurenines), thereby inhibiting T cell proliferation. Interestingly, blocking of IDO with 1-methyltrytophan reversed the suppressive effect, implicating IDO as a potential mediator in T cell suppression. Concomitantly, several candidate suppressive factors in the supernatants have also been identified using antibody arrays. However, their functions require validation. In conclusion, hESC-MSC share similar suppressive properties as BM-MSC and represent a potential cell source for clinical purposes.