Abstract
Despite mesenchymal stromal cells (MSCs) are considered as a promising source of cells to modulate immune functions on cells from innate and adaptive immune systems, their clinical use remains restricted (few number, limited in vitro expansion, absence of a full phenotypic characterization, few insights on their in vivo fate). Standardized MSCs derived in vitro from human-induced pluripotent stem (huIPS) cells, remediating part of these issues, are considered as well as a valuable tool for therapeutic approaches, but their functions remained to be fully characterized. We generated multipotent MSCs derived from huiPS cells (huiPS-MSCs), and focusing on their immunosuppressive activity, we showed that human T-cell activation in coculture with huiPS-MSCs was significantly reduced. We also observed the generation of functional CD4+ FoxP3+ regulatory T (Treg) cells. Further tested in vivo in a model of human T-cell expansion in immune-deficient NSG mice, huiPS-MSCs immunosuppressive activity prevented the circulation and the accumulation of activated human T cells. Intracytoplasmic labeling of cytokines produced by the recovered T cells showed reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines. By contrast, T cells producing IL-10 and FoxP3+-Treg cells, absent in non-treated animals, were detected in huiPS-MSCs treated mice. For the first time, these results highlight the immunosuppressive activity of the huiPS-MSCs on human T-cell stimulation with a concomitant generation of human Treg cells in vivo. They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance.
Highlights
Among the different cells potentially used in regenerative medicine, the mesenchymal stromal cells (MSCs) are viewed as an interesting source of cells, increasingly used in the treatment of various clinical contexts as well as for immunomodulation in conditions linked to auto/allo-immunity [1]
We further demonstrate that their infusion in humanized NSG mice [human peripheral blood mononuclear cell (PBMC) mouse] induced a decrease in the proportion of human CD4+ and CD8+ T cells expanding within the mice, along with a switch from a Th1 cytokine profile toward a Treg signature
These results highlight that the human-induced pluripotent stem (huiPS)-MSCs generated with our protocol shared strong similarities with in vitro maintained MSCs derived from adult tissues [2, 3]
Summary
Among the different cells potentially used in regenerative medicine, the mesenchymal stromal cells (MSCs) are viewed as an interesting source of cells, increasingly used in the treatment of various clinical contexts as well as for immunomodulation in conditions linked to auto/allo-immunity [1]. These cells are self-renewing, adhere to plastic, express characteristic surface antigens and have mesodermal. Ex vivo isolated somatic MSCs have been implicated in immune-regulatory functions on cells from both the innate and adaptive immune system. Cell-to-cell contact was shown to be involved in the T cell-inhibitory effect of MSCs, for instance, through targeting cell surface ligands of the B7 super family [5, 6]
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