人多能干细胞源性心肌细胞中脂多糖诱导的炎症反应和电生理功能障碍
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Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes.
背景与目的
严重的感染(如脓毒血症)常常导致心肌病变。目前脓毒血症性心肌病的致病机制并不清楚，因此尚无有效的治疗措施.本研究的目的是通过由人多能干细胞源性心肌细胞(hiPSC-CMs)建立的内源性炎症反应模型探究脓毒血症性心肌病的致病机制和治疗措施。
方 法
不同浓度的脂多糖采用不同处理时间处理hiPSC-CMs。本研究中采用了ELISA，FACS，qPCR以及膜片钳技术检测了hiPSC-CMs中Toll样受体4（TLR4）及其相关蛋白，CD14，脂多糖结合蛋白（LBP），Toll白介素1受体结构域衔接蛋白（TIRAP），淋巴细胞抗原96（Ly96），核因子kB（NF-kB）以及一些促炎和抗炎因子的表达和离子通道电流的变化。
结 果
hiPSC-CMs脂多糖处理6h时增加了促炎因子和趋化因子（TNF-a, IL-1ß, IL-6, CCL2, CCL5, IL-8）的表达，而在处理48h时也增加了抗炎因子（IL-10 and IL-6）的表达。脂多糖增加了hiPSC-CMs的凋亡和坏死从而导致了细胞的损伤。此外，脂多糖也通过抑制低电导的Ca2+激活K+通道电流和增强Na+/Ca2+交换体通道电流延长了动作电位时程，从而引起了细胞电功能障碍。
结 论
hiPSC-CMs具有能参与内毒素诱发的炎症反应的功能性反应系统，所以其可作为构建某些细菌诱发的心肌细胞炎症反应模型。
原始文献摘要
Yucel G, Zhao Z, El-Battrawy I, et al. Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes.[J]. Scientific reports, 2017,7(1):2935.10.1038/s41598-017-03147-4
Background: Severe infections like sepsis lead frequently to cardiomyopathy. The mechanisms are unclear and an optimal therapy for septic cardiomyopathy still lacks. The aim of this study is to establish an endotoxin-induced inflammatory model using human induced pluripotent stem cell (hiPSC) derived cardiomyocytes (hiPSC-CMs) for mechanistic and therapeutic studies.
Method:hiPSC-CMs were treated by lipopolysaccharide (LPS) in different concentrations for different times. ELISA, FACS, qPCR, and patch-clamp techniques were used for the study. TLR4 (Toll-like receptor 4) and its associated proteins, CD14, LBP (lipopolysaccharide binding protein), TIRAP (toll-interleukin 1 receptor domain containing adaptor protein), Ly96 (lymphocyte antigen 96) and nuclear factor kappa B as well as some pro-and anti-inflammatory factors are expressed in hiPSC-CMs.
Results:LPS-treatment for 6 hours increased the expression levels of pro-inflammatory and chemotactic cytokines (TNF-a, IL-1ss, IL-6, CCL2, CCL5, IL-8), whereas 48 hour-treatment elevated the expression of anti-inflammatory factors (IL-10 and IL-6). LPS led to cell injury resulting from exaggerated cell apoptosis and necrosis. Finally, LPS inhibited small conductance Ca2+-activated K+ channel currents, enhanced Na+/Ca2+-exchanger currents, prolonged action potential duration, suggesting cellular electrical dysfunctions.
Conclusion: Our data demonstrate that hiPSC-CMs possess the functional reaction system involved in endotoxin-induced inflammation and can model some bacterium-induced inflammatory responses in cardiac myocytes.
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