Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model.
Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model.
复制标题
在小鼠扩张型心肌病模型中，使用α - 半乳糖神经酰胺（αGalCer）负载的树突状细胞进行免疫调节细胞疗法可改善心力衰竭。
DOI：
10.1161/circheartfailure.122.009366
复制
发表时间：
2022-12
影响因子：
9.7
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ikeda, Masataka;Ide, Tomomi;Matsushima, Shouji;Ikeda, Soichiro;Okabe, Kosuke;Ishikita, Akihito;Tadokoro, Tomonori;Sada, Masashi;Abe, Ko;Sato, Midori;Hanada, Akiko;Arai, Shinobu;Ohtani, Kisho;Nonami, Atsushi;Mizuno, Shinichi;Morimoto, Sachio;Motohashi, Shinichiro;Akashi, Koichi;Taniguchi, Masaru;Tsutsui, Hiroyuki
关键词：
扩张型心肌病（DCM）是一种危及生命的疾病，可导致难治性心衰。一种免疫紊乱是与心力衰竭进展相关的病理生理学基础。不变性自然杀伤T （iNKT）细胞激活是缺血性心脏病的一种前瞻性治疗策略。然而，其在非缺血性心肌病（如DCM）中的疗效仍有待阐明，iNKT细胞在人体内激活的可行方式也有待验证。在体外用α-半乳糖神经酰胺对人体树突状细胞进行脉冲处理，制备α-半乳糖神经酰胺脉冲树突状细胞（α - gcdcs）。我们用α - gcdcs处理含有突变肌钙蛋白TΔK210/ΔK210的DCM小鼠，并评估iNKT细胞活化对DCM小鼠心力衰竭的影响。此外，我们研究了其在这些小鼠中治疗作用的分子基础，并分析了iNKT细胞分泌细胞因子作用下的原代心肌细胞。与野生型小鼠相比，α - gcdc可使DCM小鼠脾脏iNKT细胞数量减少，α - gcdc可激活iNKT细胞，延长DCM小鼠的生存期，并可抑制左心室射血分数下降4周，同时抑制间质纤维化。机制上，α - gcdc治疗通过上调血管生成素1 （Angpt1）表达，抑制TGF（转化生长因子）-β信号和纤维化基因的表达，恢复DCM心脏受损的血管。IFNγ（干扰素γ）通过Stat1抑制TGF-β诱导的Smad2/3信号和心肌成纤维细胞中纤维化基因的表达，并上调心肌细胞中Angpt1的表达。免疫调节细胞治疗α - gcdcs是治疗DCM心衰的一种新方法。
Dilated cardiomyopathy (DCM) is a life-threatening disease, resulting in refractory heart failure. An immune disorder underlies the pathophysiology associated with heart failure progression. Invariant natural killer T (iNKT) cell activation is a prospective therapeutic strategy for ischemic heart disease. However, its efficacy in nonischemic cardiomyopathy, such as DCM, remains to be elucidated, and the feasible modality for iNKT cell activation in humans is yet to be validated. Dendritic cells isolated from human volunteers were pulsed with α-galactosylceramide ex vivo, which were used as α-galactosylceramide-pulsed dendritic cells (αGCDCs). We treated DCM mice harboring mutated troponin TΔK210/ΔK210 with αGCDCs and evaluated the efficacy of iNKT cell activation on heart failure in DCM mice. Furthermore, we investigated the molecular basis underlying its therapeutic effects in these mice and analyzed primary cardiac cells under iNKT cell-secreted cytokines. The number of iNKT cells in the spleens of DCM mice was reduced compared with that in wild-type mice, whereas αGCDC treatment activated iNKT cells, prolonged survival of DCM mice, and prevented decline in the left ventricular ejection fraction for 4 weeks, accompanied by suppressed interstitial fibrosis. Mechanistically, αGCDC treatment suppressed TGF (transforming growth factor)-β signaling and expression of fibrotic genes and restored vasculature that was impaired in DCM hearts by upregulating angiopoietin 1 (Angpt1) expression. Consistently, IFNγ (interferon gamma) suppressed TGF-β-induced Smad2/3 signaling and the expression of fibrotic genes in cardiac fibroblasts and upregulated Angpt1 expression in cardiomyocytes via Stat1. Immunomodulatory cell therapy with αGCDCs is a novel therapeutic strategy for heart failure in DCM.