Human iPSC-derived myocardium-on-chip with capillary-like flow for personalized medicine
Human iPSC-derived myocardium-on-chip with capillary-like flow for personalized medicine
复制标题
DOI：
10.1063/1.4978468
复制
发表时间：
2017-03-01
期刊：
影响因子：
3.2
通讯作者：
Zorlutuna, Pinar
中科院分区：
文献类型：
--
作者：
Ellis, Bradley W.;Acun, Aylin;Zorlutuna, Pinar
心壁组织或心肌是预防和治疗心血管疾病的主要目标之一。动物模型还不足以模拟人类心肌，心血管药物的临床转译率非常低。此外，目前的体外人类心肌模型存在一些缺点，如缺乏与生理相关的心肌细胞共培养，缺乏3D仿生环境，以及使用非人类细胞。在这项研究中，我们通过使用3D细胞负载水凝胶结构和人类诱导多能干细胞（hiPSC）衍生的心肌细胞设计和制造心肌芯片（MOC）来解决这些缺点。MOC利用hiPSC来源的心肌细胞（iCMs）和hiPSC来源的内皮细胞（iECs）的三维空间控制共培养，整合在iCMs之间以及毛细血管样侧通道中，以更好地模拟天然心肌中的微血管。我们首先通过免疫染色、遗传和电化学分析对iCMs进行了全面表征，并通过免疫染色和比对分析对iec进行了全面表征，以确保其功能，然后将这些细胞依次植入MOC装置。我们发现iec可以在微流控装置中培养而不会失去其表型谱系承诺，并在生理水平剪切应力下与流动保持一致。我们能够在光交联聚合物的帮助下，以一种空间控制的方式将icm整合到设备中。icm在设备内的可行性和功能可达7天，并与iec集成。本研究中的iCMs和iECs来源于相同的hiPSC细胞系，基本上模拟了单个人类患者的心肌。这种装置对于个性化医学研究是必不可少的，在个性化医学研究中，不同遗传背景的患者的个体药物反应可以以生理学相关的方式进行测试。AIP出版社出版。
The heart wall tissue, or the myocardium, is one of the main targets in cardiovascular disease prevention and treatment. Animal models have not been sufficient in mimicking the human myocardium as evident by the very low clinical translation rates of cardiovascular drugs. Additionally, current in vitro models of the human myocardium possess several shortcomings such as lack of physiologically relevant co-culture of myocardial cells, lack of a 3D biomimetic environment, and the use of non-human cells. In this study, we address these shortcomings through the design and manufacture of a myocardium-on-chip (MOC) using 3D cell-laden hydrogel constructs and human induced pluripotent stem cell (hiPSC) derived myocardial cells. The MOC utilizes 3D spatially controlled co-culture of hiPSC derived cardiomyocytes (iCMs) and hiPSC derived endothelial cells (iECs) integrated among iCMs as well as in capillary-like side channels, to better mimic the microvasculature seen in native myocardium. We first fully characterized iCMs using immunostaining, genetic, and electrochemical analysis and iECs through immunostaining and alignment analysis to ensure their functionality, and then seeded these cells sequentially into the MOC device. We showed that iECs could be cultured within the microfluidic device without losing their phenotypic lineage commitment, and align with the flow upon physiological level shear stresses. We were able to incorporate iCMs within the device in a spatially controlled manner with the help of photocrosslinkable polymers. The iCMs were shown to be viable and functional within the device up to 7 days, and were integrated with the iECs. The iCMs and iECs in this study were derived from the same hiPSC cell line, essentially mimicking the myocardium of an individual human patient. Such devices are essential for personalized medicine studies where the individual drug response of patients with different genetic backgrounds can be tested in a physiologically relevant manner. Published by AIP Publishing.