title: SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts.
abstract: The generation of pluripotent stem cells by somatic cell nuclear transfer (SCNT) has recently been achieved in human cells and sparked new interest in this technology. The authors reporting this methodical breakthrough speculated that SCNT would allow the creation of patient-matched embryonic stem cells, even in patients with hereditary mitochondrial diseases. However, herein we show that mismatched mitochondria in nuclear-transfer-derived embryonic stem cells (NT-ESCs) possess alloantigenicity and are subject to immune rejection. In a murine transplantation setup, we demonstrate that allogeneic mitochondria in NT-ESCs, which are nucleus-identical to the recipient, may trigger an adaptive alloimmune response that impairs the survival of NT-ESC grafts. The immune response is adaptive, directed against mitochondrial content, and amenable for tolerance induction. Mitochondrial alloantigenicity should therefore be considered when developing therapeutic SCNT-based strategies.
authors.affiliation: TSI Laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Surgery, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.affiliation: TSI Laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: TSI Laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Stubbendorff
authors.affiliation: TSI Laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Ryo
authors.initials: R
authors.lastname: Itagaki
authors.affiliation: TSI Laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Grabosch
authors.affiliation: Newcastle University Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Greaves
authors.affiliation: Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Virus Genomics, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Grünewald
authors.affiliation: TSI Laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Hu
authors.affiliation: TSI Laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Hua
authors.affiliation: Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Maximiliansplatz 2, 91054 Erlangen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Velden
authors.affiliation: Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Surgery, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.affiliation: Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.affiliation: Department of Developmental Biology, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: TSI Laboratory, University Heart Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany; Stanford Cardiovascular Institute and Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. Electronic address: schrepfer@stanford.edu.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007109:Immunity; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D053652:Nuclear Transfer Techniques; D014184:Transplantation, Homologous
chemical_list: D000941:Antigens