Characterization and Validation of a Human 3D Cardiac Microtissue for the Assessment of Changes in Cardiac Pathology.
Characterization and Validation of a Human 3D Cardiac Microtissue for the Assessment of Changes in Cardiac Pathology.
复制标题
人类3D心脏微动物的表征和验证，以评估心脏病理变化。
DOI：
10.1038/s41598-018-28393-y
复制
发表时间：
2018-07-05
影响因子：
4.6
通讯作者：
Pointon A
中科院分区：
文献类型：
--
作者：
Archer CR;Sargeant R;Basak J;Pilling J;Barnes JR;Pointon A
尽管药物能够有效治疗疾病，但可能会引起额外的心血管副作用。心脏毒性的特征是心肌功能和/或结构的变化。近年来，功能性心脏毒性受到了广泛关注，但心肌形态损伤和/或活力丧失仍然需要改进的检测和机制见解。使用含有人诱导多能干细胞来源的心肌细胞 (hiPS-CM)、心脏内皮细胞和心脏成纤维细胞的人 3D 心脏微组织来评估它们检测药物诱导的心脏结构变化的适用性。组织学和临床病理学证实这些心脏微组织形态完整，缺乏坏死/凋亡核心并包含所有相关细胞成分。开发了评估线粒体膜电位、内质网完整性和细胞活力的高通量方法，并对 15 种 FDA 批准的结构性心脏毒素和 14 种 FDA 批准的非结构性心脏毒素进行了评估。我们报告说，心脏微组织提供了一种高通量实验模型，既能够检测临床相关浓度下心脏结构的变化，又能深入了解这种责任的表型机制。
Pharmaceutical agents despite their efficacy to treat disease can cause additional unwanted cardiovascular side effects. Cardiotoxicity is characterized by changes in either the function and/or structure of the myocardium. Over recent years, functional cardiotoxicity has received much attention, however morphological damage to the myocardium and/or loss of viability still requires improved detection and mechanistic insights. A human 3D cardiac microtissue containing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), cardiac endothelial cells and cardiac fibroblasts was used to assess their suitability to detect drug induced changes in cardiac structure. Histology and clinical pathology confirmed these cardiac microtissues were morphologically intact, lacked a necrotic/apoptotic core and contained all relevant cell constituents. High-throughput methods to assess mitochondrial membrane potential, endoplasmic reticulum integrity and cellular viability were developed and 15 FDA approved structural cardiotoxins and 14 FDA approved non-structural cardiotoxins were evaluated. We report that cardiac microtissues provide a high-throughput experimental model that is both able to detect changes in cardiac structure at clinically relevant concentrations and provide insights into the phenotypic mechanisms of this liability.
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影响因子：
120.1
作者：
Cook, David;Brown, Dearg;Pangalos, Menelas N.
通讯作者：
Pangalos, Menelas N.
影响因子：
3.8
作者：
Hasinoff, Brian B.
通讯作者：
Hasinoff, Brian B.
影响因子：
5.9
作者：
Kijlstra JD;Hu D;Mittal N;Kausel E;van der Meer P;Garakani A;Domian IJ
通讯作者：
Domian IJ
影响因子：
16.1
作者：
Kurokawa YK;George SC
通讯作者：
George SC
影响因子：
3.5
作者：
Blanca, Antonio J.;Ruiz-Armenta, Maria V.;Vazquez, Carmen M.
通讯作者：
Vazquez, Carmen M.