Wharton’s jelly mesenchymal stromal cells inhibit T-cell proliferation by synergistic IDO and mitochondrial transfer mechanisms

AbstractBackgroundWharton's jelly mesenchymal stem cells (WJ-MSCs) are multipotent stromal cells derived from the umbilical cord that may have therapeutic potential in immune-related diseases. In the context of allogeneic stem cell transplantation, WJ-MSCs represent a good candidate for graft versus host disease (GVHD) prophylaxis and treatment.MethodsHerein, we investigated the immunomodulatory mechanisms of WJ-MSCs, produced at clinical grade according to our Good Manufacturing Practice,in vitroand in an experimental GVHD xenogeneic mouse model.ResultsWe observed that repeated injections of IFN-γ-primed WJ-MSCs increased recipient survival and reduced histological GVHD scores while transiently colocalizing with T cells. We then demonstrated that WJ-MSCs were able to inhibit T-cell proliferationin vitrothrough indoleamine 2,3-dioxygenase (IDO) and mitochondrial transfer to T cells. Our results suggest that these processes act synergistically, since IDO is needed for the optimal effect of WJ-MSC-mediated mitochondrial transfer on T-cell metabolism, which is characterized by a switch from glycolysis toward oxidative phosphorylation.ConclusionOverall, our data indicate that IFN-γ-primed WJ-MSCs are able to control GVHD by reprogramming the metabolism of T cells, and we report for the first time a synergistic interplay between IDO and contact-dependent mitochondrial transfer, providing new insights for the treatment of immune-related diseases.