title: Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance.
abstract: The exact nature of the immune response elicited by autologous-induced pluripotent stem cell (iPSC) progeny is still not well understood. Here we show in murine models that autologous iPSC-derived endothelial cells (iECs) elicit an immune response that resembles the one against a comparable somatic cell, the aortic endothelial cell (AEC). These cells exhibit long-term survival in vivo and prompt a tolerogenic immune response characterized by elevated IL-10 expression. In contrast, undifferentiated iPSCs elicit a very different immune response with high lymphocytic infiltration and elevated IFN-γ, granzyme-B and perforin intragraft. Furthermore, the clonal structure of infiltrating T cells from iEC grafts is statistically indistinguishable from that of AECs, but is different from that of undifferentiated iPSC grafts. Taken together, our results indicate that the differentiation of iPSCs results in a loss of immunogenicity and leads to the induction of tolerance, despite expected antigen expression differences between iPSC-derived versus original somatic cells.
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA [4].
authors.forename: Patricia E
authors.initials: PE
authors.lastname: de Almeida
authors.affiliation: 1] Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2].
authors.forename: Everett H
authors.initials: EH
authors.lastname: Meyer
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA [4].
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Kooreman
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Diecke
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Devaveena
authors.initials: D
authors.lastname: Dey
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Sanchez-Freire
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Hu
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Antje
authors.initials: A
authors.lastname: Ebert
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Odegaard
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Mordwinkin
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Brouwer
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lo
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Montoro
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.affiliation: 1] Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California 94305-5323, USA [2] Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305-5323, USA [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5323, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D053804:Granzymes / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D057026:Induced Pluripotent Stem Cells / Q000276:immunology / Q000637:transplantation*; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D054353:Perforin / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*
chemical_list: D054353:Perforin; D016753:Interleukin-10; D053804:Granzymes