Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model
Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model
复制标题
DOI：
10.1253/circj.cj-16-0541
复制
发表时间：
2017-01-01
影响因子：
3.3
通讯作者：
Hamaoka, Kenji
中科院分区：
文献类型：
--
作者：
Ikeda, Kazuyuki;Mizoro, Yasutaka;Hamaoka, Kenji
背景：大约10-20%的川崎病（KD）患者对静脉注射免疫球蛋白（IVIG）治疗有耐药性。此外，这些患者患冠状动脉异常的风险特别高。利用患者白细胞分析了KD患者抗IVIG的机制，但没有使用患者血管内皮细胞（ECs）。本研究利用诱导多能干细胞（iPSC）疾病模型阐明了KD中IVIG耐药的机制。方法与结果：对2例ivig耐药和2例ivig应答的KD患者的皮肤成纤维细胞或外周血单个核细胞进行了6种重编程因子的外源性载体介导的重编程。KD患者来源的iPSCs分化为ECs （iPSC-ECs）。通过rna测序分析比较了ivig耐药和ivig应答的KD患者产生的iPSC-ECs的基因表达谱。我们发现，在ivig耐药KD患者的iPSC-ECs中，CXCL12的表达显著上调。此外，基因集富集分析（GSEA）显示，参与白细胞介素(IL)-6信号传导的基因集也上调。结论：本文报道了首个基于ipsc的KD模型。我们的机制分析表明，在白细胞转运中起作用的CXCL12是IVIG耐药和KD严重程度的关键候选分子。他们还表明，il -6相关基因的上调可能参与了这一发病机制。
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.