BACKGROUND: Induced pluripotent stem cells (iPSCs)-technology provides new opportunities in regenerative medicine to generate grafts from donors for transplantation. However, particularly when allogeneic iPSCs are used, immune suppression is required to avoid rejection of iPSCs-derived grafts. In this study, we examine a concept that immunosuppressive cells can be induced from iPSCs which may contribute to prolong survival of same iPSCs-derived allografts.

METHODS: Mouse iPSCs were generated from mouse fibroblasts and then differentiated into immunosuppressive cells by using culture protocol including GM-CSF, M-CSF, IL-4 and LPS. Adherent clusters were collected and examined for the ability to suppress allogeneic T and B cell responses, and the contribution to prolong allogeneic graft-survival in a transplantation model.

RESULTS: Myeloid cells with immunosuppressive features were successfully induced from iPSCs, and thus referred to as iPSCs-derived suppressive cells (iPS-SCs). iPS-SCs resemble macrophages in terms of cell surface molecules(such as CD14, CD11b, F4/80, CD206 and MHC class II) and macrophage-related gene expressions including Nos2. iPS-SCs efficiently suppressed allogeneic T and B cell proliferation in a nitric oxide dependent manner. Furthermore, iPS-SCs were found to substantially prolong survival of iPSCs-derived grafts such as embryoid bodies and cardiomyocytes in in vivo allogeneic transplantation model.

CONCLUSIONS: A certain fraction of macrophage-like cells with immunosuppressive functions can be generated from donor iPSCs, which contribute to prolong survival of same iPSCs-derived grafts in allogeneic recipients. These results suggest a new immunosuppressive strategy of combined donor iPSCs-derived graft and immunosuppressive cells transplantation in regenerative medicine using iPSCs.

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