New Immunosuppressive Cell Therapy to Prolong Survival of Induced Pluripotent Stem Cell–Derived Allografts

Hajime Sasaki, Haruka Wada, Muhammad Baghdadi, Hyuma Tsuji, Ryo Otsuka, Ken Morita, Nobuo Shinohara, Ken-ichiro Seino

Induced pluripotent stem cell (iPSC) 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 iPSC-derived grafts. In this study, we examine a concept that protection of iPSCs-derived allografts can be achieved when transplantation is accompanied with the administration of immunosuppressive cells generated from the same iPSCs resource. Mouse iPSCs were differentiated into immunosuppressive cells by a culture protocol using granulocyte macrophage-colony-stimulating factor, macrophage-colony-stimulating factor, IL-4, and lipopolysaccharide. Adherent clusters were collected and examined for the ability to suppress allogeneic T- and B-cell responses, as well as for the contribution to prolonged allogeneic graft survival in transplantation models. Myeloid cells with immunosuppressive features were successfully induced from iPSCs, and thus referred to as iPSC-derived suppressor cells (iPS-SCs). The iPS-SCs resemble macrophages in terms of cell surface molecules and gene expressions. Furthermore, iPS-SCs efficiently suppressed allogeneic T- and B-cell proliferation in a nitric oxide-dependent manner, and iPS-SCs were found to suppress alloantibody production and prolong substantially the survival of iPSC-derived grafts, such as embryoid bodies and cardiomyocytes, in in vivo allogeneic transplantation models. A certain fraction of macrophage-like cells with immunosuppressive functions can be generated from donor iPSCs, which contribute to the prolonged survival of grafts derived from the same iPSCs in allogeneic recipients. These results suggest a new immunosuppressive strategy of combined donor iPSC-derived graft and immunosuppressive cell transplantation in regenerative medicine using iPSCs.