Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model

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  • Ikeda Kazuyuki
    Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Mizoro Yasutaka
    Center for iPS Cell Research and Application (CiRA), Kyoto University Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University
  • Ameku Tomonaga
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Nomiya Yui
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Mae Shin-Ichi
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Matsui Satoshi
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Kuchitsu Yuki
    Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Suzuki Chinatsu
    Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Hamaoka-Okamoto Akiko
    Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Yahata Tomoyo
    Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Sone Masakatsu
    Department of Metabolic Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine
  • Okita Keisuke
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Watanabe Akira
    Center for iPS Cell Research and Application (CiRA), Kyoto University Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University
  • Osafune Kenji
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Hamaoka Kenji
    Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine

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<p>Background:Approximately 10–20% of Kawasaki disease (KD) patients are resistant to intravenous immunoglobulin (IVIG) treatment. Further, these patients are at a particularly high risk of having coronary artery abnormalities. The mechanisms of IVIG resistance in KD have been analyzed using patient leukocytes, but not patient vascular endothelial cells (ECs). The present study clarifies the mechanisms of IVIG resistance in KD using an induced pluripotent stem cell (iPSC) disease model.</p><p>Methods and Results:Dermal fibroblasts or peripheral blood mononuclear cells from 2 IVIG-resistant and 2 IVIG-responsive KD patients were reprogrammed by the episomal vector-mediated transduction of 6 reprogramming factors. KD patient-derived iPSCs were differentiated into ECs (iPSC-ECs). The gene expression profiles of iPSC-ECs generated from IVIG-resistant and IVIG-responsive KD patients were compared by RNA-sequencing analyses. We found that the expression ofCXCL12was significantly upregulated in iPSC-ECs from IVIG-resistant KD patients. Additionally, Gene Set Enrichment Analysis (GSEA) revealed that gene sets involved in interleukin (IL)-6 signaling were also upregulated.</p><p>Conclusions:The first iPSC-based model for KD is reported here. Our mechanistic analyses suggest thatCXCL12, which plays a role in leukocyte transmigration, is a key molecule candidate for IVIG resistance and KD severity. They also indicate that an upregulation of IL-6-related genes may be involved in this pathogenesis.</p>

収録刊行物

  • Circulation Journal

    Circulation Journal 81 (1), 110-118, 2017

    一般社団法人 日本循環器学会

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