Investigating why transplanted autologous induced pluripotent stem cells (iPSCs) sometimes get rejected, Deuse and Hu et al. found that ex vivo reprogramming and/or culturing of iPSCs leads to a high rate of mutations in mitochondrial (mt)DNA. In mice, mt-neoantigen-expressing iPSCs provoked immune responses (dependent on MHC presentation) and showed reduced cellular survival. Some mtDNA SNPs in human iPSCs produced neoantigens that were sufficient to trigger specific immune responses in PBMCs. Emergence of mt-neoantigens was not observed in longitudinal PBMC samples, which may reflect immunoediting in vivo.
The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.
Author Info: (1) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA, USA. (2) Depa
Author Info: (1) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA, USA. (2) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA, USA. Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany. Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, partner site Hamburg/Kiel/Luebeck, Hamburg, Germany. (3) Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA. Laboratory of Transplantation Genomics, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. (4) Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, University Transplant Center, Hamburg, Germany. (5) Departments of Otolaryngology, Head and Neck Surgery and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Chan Zuckerberg Biohub, San Francisco, CA, USA. (6) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA, USA. Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, partner site Hamburg/Kiel/Luebeck, Hamburg, Germany. (7) Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (8) Laboratory of Transplantation Genomics, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. (9) Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA. (10) Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA. (11) Laboratory of Transplantation Genomics, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. (12) Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA. (13) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA, USA. Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany. Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, partner site Hamburg/Kiel/Luebeck, Hamburg, Germany. (14) Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, University Transplant Center, Hamburg, Germany. (15) Department of Anaesthesia, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (16) Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany. Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, partner site Hamburg/Kiel/Luebeck, Hamburg, Germany. (17) Laboratory of Transplantation Genomics, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. (18) Department of Developmental Biology, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (19) Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA, USA. Sonja.Schrepfer@ucsf.edu. Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany. Sonja.Schrepfer@ucsf.edu. Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, partner site Hamburg/Kiel/Luebeck, Hamburg, Germany. Sonja.Schrepfer@ucsf.edu. Sana Biotechnology Inc., South San Francisco, CA, USA. Sonja.Schrepfer@ucsf.edu.
