| Summary: | Summary: 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. : T cells and antibodies or NK cells reject HLA-I-incompatible or HLA-I-deficient cells, respectively. Sugimoto and colleagues produced HLA-I null platelets from iPSCs in a clinically applicable system and found that platelets can circulate even in human NK cell-reconstituted mice. Potentially, universal HLA-KO platelets could treat patients suffering from platelet transfusion refractoriness caused by HLA-I incompatibility. Keywords: platelet, megakaryocyte, iPSC, HLA class I, natural killer cell, regenerative medicine, imMKCL, platelet transfusion, refractoriness, MSTRG mice, IL-15
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