title: Induced pluripotent stem cell-derived gamete-associated proteins incite rejection of induced pluripotent stem cells in syngeneic mice.
abstract: The safety of induced pluripotent stem cells (iPSCs) in autologous recipients has been questioned after iPSCs, but not embryonic stem cells (ESCs), were reported to be rejected in syngeneic mice. This important topic has remained controversial because there has not been a mechanistic explanation for this phenomenon. Here, we hypothesize that iPSCs, but not ESCs, readily differentiate into gamete-forming cells that express meiotic antigens normally found in immune-privileged gonads. Because peripheral blood T cells are not tolerized to these antigens in the thymus, gamete-associated-proteins (GAPs) sensitize T cells leading to rejection. Here, we provide evidence that GAPs expressed in iPSC teratomas, but not in ESC teratomas, are responsible for the immunological rejection of iPSCs. Furthermore, silencing the expression of Stra8, 'the master regulator of meiosis', in iPSCs, using short hairpin RNA led to significant abrogation of the rejection of iPSCs, supporting our central hypothesis that GAPs expressed after initiation of meiosis in iPSCs were responsible for rejection. In contrast to iPSCs, iPSC-derivatives, such as haematopoietic progenitor cells, are able to engraft long-term into syngeneic recipients because they no longer express GAPs. Our findings, for the first time, provide a unifying explanation of why iPSCs, but not ESCs, are rejected in syngeneic recipients, ending the current controversy on the safety of iPSCs and their derivatives.
authors.affiliation: Department of Internal Medicine, Division of Immunology, University of Iowa & VAMC Iowa City, Iowa City, IA, USA.|Predictive Model Research Centre, Korea Institute of Toxicology, Yuseong-gu, Daejeon, Korea.
authors.forename: Eun-Mi
authors.identifier: 0000-0002-5110-9909
authors.initials: EM
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Division of Immunology, University of Iowa & VAMC Iowa City, Iowa City, IA, USA.|Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA.
authors.forename: Gohar
authors.initials: G
authors.lastname: Manzar
authors.affiliation: Department of Internal Medicine, Division of Immunology, University of Iowa & VAMC Iowa City, Iowa City, IA, USA.|Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Zavazava
mesh_terms: D000818:Animals; D002460:Cell Line; D006084:Graft Rejection / Q000276:immunology*; D057026:Induced Pluripotent Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology; D014185:Transplantation, Isogeneic
chemical_list: D008565:Membrane Proteins
keywords: CD4+ T cells; gamete-associated proteins; rejection of induced pluripotent stem cells