PMID- 31883921 OWN - NLM STAT- MEDLINE DCOM- 20200922 LR - 20210110 IS - 2213-6711 (Electronic) IS - 2213-6711 (Linking) VI - 14 IP - 1 DP - 2020 Jan 14 TI - iPSC-Derived Platelets Depleted of HLA Class I Are Inert to Anti-HLA Class I and Natural Killer Cell Immunity. PG - 49-59 LID - S2213-6711(19)30414-X [pii] LID - 10.1016/j.stemcr.2019.11.011 [doi] AB - The ex vivo production of platelets depleted of human leukocyte antigen class I (HLA-I) could serve as a universal measure to overcome platelet transfusion refractoriness caused by HLA-I incompatibility. Here, we developed human induced pluripotent cell-derived HLA-I-deficient platelets (HLA-KO iPLATs) in a clinically applicable imMKCL system by genetic manipulation and assessed their immunogenic properties including natural killer (NK) cells, which reject HLA-I downregulated cells. HLA-KO iPLATs were deficient for all HLA-I but did not elicit a cytotoxic response by NK cells in vitro and showed circulation equal to wild-type iPLATs upon transfusion in our newly established Hu-NK-MSTRG mice reconstituted with human NK cells. Additionally, HLA-KO iPLATs successfully circulated in an alloimmune platelet transfusion refractoriness model of Hu-NK-MISTRG mice. Mechanistically, the lack of NK cell-activating ligands on platelets may be responsible for evading the NK cell response. This study revealed the unique non-immunogenic property of platelets and provides a proof of concept for the clinical application of HLA-KO iPLATs. CI - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Suzuki, Daisuke AU - Suzuki D AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Flahou, Charlotte AU - Flahou C AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Yoshikawa, Norihide AU - Yoshikawa N AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Stirblyte, Ieva AU - Stirblyte I AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Hayashi, Yoshikazu AU - Hayashi Y AD - International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan. FAU - Sawaguchi, Akira AU - Sawaguchi A AD - Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan. FAU - Akasaka, Marina AU - Akasaka M AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Nakamura, Sou AU - Nakamura S AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Higashi, Natsumi AU - Higashi N AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Xu, Huaigeng AU - Xu H AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Matsumoto, Takuya AU - Matsumoto T AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Fujio, Kosuke AU - Fujio K AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co. Ltd., Tokushima 771-0192, Japan. FAU - Manz, Markus G AU - Manz MG AD - Department of Hematology, University and University Hospital Zurich, 8091 Zurich, Switzerland. FAU - Hotta, Akitsu AU - Hotta A AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. FAU - Takizawa, Hitoshi AU - Takizawa H AD - International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan. FAU - Eto, Koji AU - Eto K AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Department of Regenerative Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. Electronic address: kojieto@cira.kyoto-u.ac.jp. FAU - Sugimoto, Naoshi AU - Sugimoto N AD - Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. Electronic address: naoshi.sugi@cira.kyoto-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191226 PL - United States TA - Stem Cell Reports JT - Stem cell reports JID - 101611300 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (beta 2-Microglobulin) SB - IM MH - Animals MH - Blood Platelets/*cytology/*metabolism MH - *Cell Differentiation MH - Cytotoxicity, Immunologic/genetics/immunology MH - Gene Knockout Techniques MH - Histocompatibility Antigens Class I/genetics/*immunology MH - Humans MH - Induced Pluripotent Stem Cells/*cytology MH - Killer Cells, Natural/*immunology/*metabolism MH - Lymphocyte Activation/genetics/immunology MH - Mice MH - Mice, Knockout MH - beta 2-Microglobulin/deficiency/genetics PMC - PMC6962657 OTO - NOTNLM OT - HLA class I OT - IL-15 OT - MSTRG mice OT - iPSC OT - imMKCL OT - megakaryocyte OT - natural killer cell OT - platelet OT - platelet transfusion OT - refractoriness OT - regenerative medicine EDAT- 2019/12/31 06:00 MHDA- 2020/09/23 06:00 PMCR- 2019/12/26 CRDT- 2019/12/30 06:00 PHST- 2019/04/27 00:00 [received] PHST- 2019/11/29 00:00 [revised] PHST- 2019/11/29 00:00 [accepted] PHST- 2019/12/31 06:00 [pubmed] PHST- 2020/09/23 06:00 [medline] PHST- 2019/12/30 06:00 [entrez] PHST- 2019/12/26 00:00 [pmc-release] AID - S2213-6711(19)30414-X [pii] AID - 10.1016/j.stemcr.2019.11.011 [doi] PST - ppublish SO - Stem Cell Reports. 2020 Jan 14;14(1):49-59. doi: 10.1016/j.stemcr.2019.11.011. Epub 2019 Dec 26.