Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity.
Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity.
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DOI：
10.3389/fphar.2021.613837
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发表时间：
2021
影响因子：
5.6
通讯作者：
Wu JC
中科院分区：
文献类型：
--
作者：
Tu C;Cunningham NJ;Zhang M;Wu JC
评估潜在的血管损伤是药物开发过程中安全性研究的重要组成部分。血管责任问题是临床前研究期间药物终止的重要原因。目前，血管毒性的临床前评估主要依赖于动物模型的使用。然而，越来越多的证据表明动物毒性和人类毒性之间存在显着差异，这使人们对动物模型对于此类安全性研究的临床相关性产生了怀疑。虽然造成这种差异的原因预计是多因素的，但物种差异可能是一个关键因素。因此，基于人类的模型是解决这个问题的理想解决方案，人类诱导多能干细胞（iPSC）的出现使这一解决方案成为可能。特别是，该领域的最新进展现在允许从 iPSC 有效生成各种血管细胞（例如内皮细胞、平滑肌细胞和周细胞）。使用这些细胞，建立了不同的血管模型，从简单的二维培养物到高度复杂的血管类器官和微流体装置。使用这些模型进行的毒性测试可以在分子（例如促炎细胞因子的分泌）、细胞（例如细胞凋亡）以及在某些情况下组织（例如内皮屏障功能障碍）水平上概括血管病理学的关键方面。这些令人鼓舞的数据为继续努力探索、优化和验证血管毒理学 iPSC 技术提供了理由。
Evaluation of potential vascular injury is an essential part of the safety study during pharmaceutical development. Vascular liability issues are important causes of drug termination during preclinical investigations. Currently, preclinical assessment of vascular toxicity primarily relies on the use of animal models. However, accumulating evidence indicates a significant discrepancy between animal toxicity and human toxicity, casting doubt on the clinical relevance of animal models for such safety studies. While the causes of this discrepancy are expected to be multifactorial, species differences are likely a key factor. Consequently, a human-based model is a desirable solution to this problem, which has been made possible by the advent of human induced pluripotent stem cells (iPSCs). In particular, recent advances in the field now allow the efficient generation of a variety of vascular cells (e.g., endothelial cells, smooth muscle cells, and pericytes) from iPSCs. Using these cells, different vascular models have been established, ranging from simple 2D cultures to highly sophisticated vascular organoids and microfluidic devices. Toxicity testing using these models can recapitulate key aspects of vascular pathology on molecular (e.g., secretion of proinflammatory cytokines), cellular (e.g., cell apoptosis), and in some cases, tissue (e.g., endothelium barrier dysfunction) levels. These encouraging data provide the rationale for continuing efforts in the exploration, optimization, and validation of the iPSC technology in vascular toxicology.
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影响因子：
16.6
作者：
Chen, Jun;Kang, Dawon;Xu, Jing;Lake, Marc;Hogan, James O.;Sun, Chaohong;Walter, Karl;Yao, Betty;Kim, Donghee
通讯作者：
Kim, Donghee
影响因子：
48
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Wu, Joseph C.
影响因子：
4.1
作者：
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通讯作者：
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影响因子：
64.5
作者：
Altschuler SJ;Wu LF
通讯作者：
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影响因子：
24
作者：
Garg, Priyanka;Oikonomopoulos, Angelos;Wu, Joseph C.
通讯作者：
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