A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues.
A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues.
复制标题
DOI：
10.1038/s41598-021-89478-9
复制
发表时间：
2021-05-13
影响因子：
4.6
通讯作者：
Coulombe KLK
中科院分区：
文献类型：
--
作者：
Kofron CM;Kim TY;Munarin F;Soepriatna AH;Kant RJ;Mende U;Choi BR;Coulombe KLK
药物、工业化学品和环境毒物的潜在毒性可能是严重的，甚至危及生命，这就需要对人类对化学化合物的反应进行彻底的评估。准确预测心律失常和心源性猝死的风险对于确定安全性特征至关重要。目前可用的方法具有局限性，包括专注于单一选择离子通道，在体外和体内使用非人类物种，以及有限的直接生理翻译。我们已经在三维微组织中使用人诱导多能干细胞衍生的心肌细胞和人心脏成纤维细胞，提高了用于评估促心律失常心脏毒性的体外平台的稳健性和可重复性。使用自动化算法和心脏动作电位的8个综合评价指标的统计分析，我们证明了组织工程化的人类心脏微组织对生理刺激的反应适当，并有效区分表现出hERG通道阻滞的高风险和低风险化合物（分别为E4031和雷诺嗪）。此外，我们表明，环境内分泌干扰物双酚A（BPA）在纳摩尔范围内引起人类动作电位的急性和敏感的干扰。因此，这种新型的人体3D体外促代谢风险评估平台解决了环境和药物化合物心脏毒性测试的关键需求，并可用于建立安全的人体暴露水平。
Cardiotoxicity of pharmaceutical drugs, industrial chemicals, and environmental toxicants can be severe, even life threatening, which necessitates a thorough evaluation of the human response to chemical compounds. Predicting risks for arrhythmia and sudden cardiac death accurately is critical for defining safety profiles. Currently available approaches have limitations including a focus on single select ion channels, the use of non-human species in vitro and in vivo, and limited direct physiological translation. We have advanced the robustness and reproducibility of in vitro platforms for assessing pro-arrhythmic cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts in 3-dimensional microtissues. Using automated algorithms and statistical analyses of eight comprehensive evaluation metrics of cardiac action potentials, we demonstrate that tissue-engineered human cardiac microtissues respond appropriately to physiological stimuli and effectively differentiate between high-risk and low-risk compounds exhibiting blockade of the hERG channel (E4031 and ranolazine, respectively). Further, we show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range. Thus, this novel human 3D in vitro pro-arrhythmic risk assessment platform addresses critical needs in cardiotoxicity testing for both environmental and pharmaceutical compounds and can be leveraged to establish safe human exposure levels.
登录
查看更多内容
人类3D心脏微动物的表征和验证，以评估心脏病理变化。
影响因子：
4.6
作者：
Archer CR;Sargeant R;Basak J;Pilling J;Barnes JR;Pointon A
通讯作者：
Pointon A
影响因子：
3.4
作者：
Clay, JR;Ogbaghebriel, A;Shrier, A
通讯作者：
Shrier, A
影响因子：
--
作者：
Ebinger, Matthew W;Krishnan, Subramaniam;Schuger, Claudio D
通讯作者：
Schuger, Claudio D
在脑膜心律失常风险评估中优化硅心细胞模型。
影响因子：
4
作者：
Dutta S;Chang KC;Beattie KA;Sheng J;Tran PN;Wu WW;Wu M;Strauss DG;Colatsky T;Li Z
通讯作者：
Li Z
影响因子：
4.9
作者：
Achilli, Toni-Marie;McCalla, Stephanie;Morgan, Jeffrey R.
通讯作者：
Morgan, Jeffrey R.