Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells.
Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells.
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DOI：
10.1039/d3lc00745f
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发表时间：
2024-01
期刊：
影响因子：
6.1
通讯作者：
M. Mozneb;Amelia Jenkins;S. Sances;Stephany Pohlman;Michael J. Workman;D. West;Briana Ondatje;Kareem El-Ghazawi;Amanda Woodbury;Veronica J Garcia;Shachi Patel;Madelyn Arzt;F. Dezem;Alexander H Laperle;V. A. Moser;Ritchie Ho;Nur Yucer;Jasmine Plummer;Robert J Barrett;Clive N. Svendsen;Arun Sharma
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作者：
M. Mozneb;Amelia Jenkins;S. Sances;Stephany Pohlman;Michael J. Workman;D. West;Briana Ondatje;Kareem El-Ghazawi;Amanda Woodbury;Veronica J Garcia;Shachi Patel;Madelyn Arzt;F. Dezem;Alexander H Laperle;V. A. Moser;Ritchie Ho;Nur Yucer;Jasmine Plummer;Robert J Barrett;Clive N. Svendsen;Arun Sharma
心血管毒性会导致药物不良反应，并可能导致药物从医药市场上撤出。癌症治疗可引起危及生命的心血管副作用，如心律失常、肌细胞死亡或血管功能障碍。新技术使心脏毒性化合物能够在药物开发的早期被发现。人诱导多能干细胞（hiPSC）衍生的心肌细胞（CM）和血管内皮细胞（EC）可以筛选药物诱导的心血管细胞功能和存活的改变。然而，大多数现有的用于心血管药物毒性的hiPSC模型利用在静态培养物中生长的二维未成熟细胞。机械地询问心脏毒性的改进的体外模型将在整合系统中利用更多的成体样成熟hiPSC衍生细胞，由此毒性药物和保护剂可以在代表全身血管系统的hiPSC-EC和代表心肌（心肌）的hiPSC-CM之间流动。这样的模型将可用于测试化疗药物如VEGFR 2/PDGFR抑制性酪氨酸激酶抑制剂（VPTKI）的多谱系心脏毒性。在这里，我们开发了一种多谱系、完全整合的心血管器官芯片，可以增强hiPSC-EC和hiPSC-CM的功能和遗传成熟度，模拟内皮屏障渗透性，并证明长期功能稳定性。这种微流体器官芯片在单独的通道上容纳hiPSC-CM和hiPSC-EC，这些通道可以经受主动流体流动和有节奏的生物力学拉伸。我们证明了这种心血管器官芯片作为评估多谱系VPTKI毒性的预测平台的实用性。这项研究可能会导致开发新的模式，用于评估和预防癌症治疗引起的心脏毒性。
Cardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and vascular endothelial cells (ECs) can screen for drug-induced alterations in cardiovascular cell function and survival. However, most existing hiPSC models for cardiovascular drug toxicity utilize two-dimensional, immature cells grown in static culture. Improved in vitro models to mechanistically interrogate cardiotoxicity would utilize more adult-like, mature hiPSC-derived cells in an integrated system whereby toxic drugs and protective agents can flow between hiPSC-ECs that represent systemic vasculature and hiPSC-CMs that represent heart muscle (myocardium). Such models would be useful for testing the multi-lineage cardiotoxicities of chemotherapeutic drugs such as VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs). Here, we develop a multi-lineage, fully-integrated, cardiovascular organ-chip that can enhance hiPSC-EC and hiPSC-CM functional and genetic maturity, model endothelial barrier permeability, and demonstrate long-term functional stability. This microfluidic organ-chip harbors hiPSC-CMs and hiPSC-ECs on separate channels that can be subjected to active fluid flow and rhythmic biomechanical stretch. We demonstrate the utility of this cardiovascular organ-chip as a predictive platform for evaluating multi-lineage VPTKI toxicity. This study may lead to the development of new modalities for the evaluation and prevention of cancer therapy-induced cardiotoxicity.