Transcriptional analysis of intravenous immunoglobulin resistance in Kawasaki disease using an induced pluripotent stem cell disease model

Ikeda, K.; Mizoro, Yasutaka; Ameku, T.; Nomiya, Y.; Mae, S.; Matsui, S.; Kuchitsu, Y.; Suzuki, C.; Hamaoka-Okamoto, A.; Yahata, T.; Sone, M.; Okita, K.; Watanabe, A.; Osafune, K.; Hamaoka, K.

doi:10.1253/circj.CJ-16-0541

Article (Scientific journals)

Transcriptional analysis of intravenous immunoglobulin resistance in Kawasaki disease using an induced pluripotent stem cell disease model

Ikeda, K.; Mizoro, Yasutaka; Ameku, T. et al.

2017 • In Circulation Journal, 81 (1), p. 110-118

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/247962

DOI
10.1253/circj.CJ-16-0541

PubMed
27867156

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Keywords :

Endothelial cells differentiated from induced pluripotent stem cell (iPSC-ECs); Induced pluripotent stem cell (iPSC); Intravenous immunoglobulin (IVIG) resistance; Kawasaki disease; CXCL12 protein, human; IL6 protein, human; Article; RNA sequence; Adolescent; Cells, Cultured; Chemokine CXCL12; Child; Drug Resistance; Female; Humans; Immunoglobulins, Intravenous; Induced Pluripotent Stem Cells; Interleukin-6; Male; Models, Biological; Mucocutaneous Lymph Node Syndrome; Transcription, Genetic

Abstract :

[en] 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. 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 of CXCL12 was 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. Conclusions: The first iPSC-based model for KD is reported here. Our mechanistic analyses suggest that CXCL12, 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. © 2017, Japanese Circulation Society. All rights reserved.

Disciplines :

Genetics & genetic processes

Author, co-author :

Ikeda, K.; Kyoto Prefectural University of Medicine > Graduate School of Medical Science > Department of Pediatric Cardiology and Nephrology

Mizoro, Yasutaka ; Kyoto University > Center for iPS Cell Research and Application

Ameku, T.; Kyoto University > Center for iPS Cell Research and Application

Nomiya, Y.; Kyoto University > Center for iPS Cell Research and Application

Mae, S.; Kyoto University > Center for iPS Cell Research and Application

Matsui, S.; Kyoto University > Center for iPS Cell Research and Application

Kuchitsu, Y.; Kyoto Prefectural University of Medicine > Graduate School of Medical Science > Department of Pediatric Cardiology and Nephrology

Suzuki, C.; Kyoto Prefectural University of Medicine > Graduate School of Medical Science > Department of Pediatric Cardiology and Nephrology

Hamaoka-Okamoto, A.; Kyoto Prefectural University of Medicine > Graduate School of Medical Science > Department of Pediatric Cardiology and Nephrology

Yahata, T.; Kyoto Prefectural University of Medicine > Graduate School of Medical Science > Department of Pediatric Cardiology and Nephrology

More authors (5 more)

Language :

English

Title :

Transcriptional analysis of intravenous immunoglobulin resistance in Kawasaki disease using an induced pluripotent stem cell disease model

Publication date :

December 2017

Journal title :

Circulation Journal

ISSN :

1346-9843

eISSN :

1347-4820

Publisher :

Japanese Circulation Society

Volume :

Issue :

Pages :

110-118

Peer reviewed :

Peer Reviewed verified by ORBi

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since 03 June 2020

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