Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells.
Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells.
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DOI：
10.1016/j.biomaterials.2018.02.024
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发表时间：
2018-05
期刊：
影响因子：
14
通讯作者：
Costa KD
中科院分区：
文献类型：
--
作者：
Li RA;Keung W;Cashman TJ;Backeris PC;Johnson BV;Bardot ES;Wong AOT;Chan PKW;Chan CWY;Costa KD
组织工程师和干细胞生物学家在创建人类心肌或排列单层的简化模型方面取得了令人兴奋的进展，以帮助弥合实验动物和临床试验之间长期存在的差距。然而，现有的人体体外系统还没有提供作为泵的心脏性能的直接测量。在这里，我们开发了下一代泵送人体心室的体外仿生模型，并展示了其药物测试的能力。我们利用嵌入胶原基细胞外基质水凝胶中的人多能干细胞 (hPSC) 衍生的心室心肌细胞 (hvCM)，设计了三维 (3D) 机电耦合、流体喷射微型人心室样心脏类器官室 (hvCOC)。结构特征显示有组织的肌节具有肌原纤维微结构。转录本和 RNA-seq 分析显示，与相同组成细胞的低阶 2D 和 3D 培养物相比，hvCOC 中关键的 Ca2+ 处理、离子通道和心脏特异性蛋白上调。测量了临床上重要的、生理上复杂的收缩参数，如射血分数、发展压力和每搏功，以及电生理特性，包括动作电位和传导速度：hvCOC 显示了自体心室的关键分子和生理特征，并显示出对一系列药物干预（包括正性和负性肌力药物）的预期机械和电生理反应。我们的结论是，这种“罐子里的人类心脏”技术可以通过在药物开发的早期阶段提供人类特异性的临床前数据来促进药物发现过程。
Tissue engineers and stem cell biologists have made exciting progress toward creating simplified models of human heart muscles or aligned monolayers to help bridge a longstanding gap between experimental animals and clinical trials. However, no existing human in vitro systems provide the direct measures of cardiac performance as a pump. Here, we developed a next-generation in vitro biomimetic model of pumping human heart chamber, and demonstrated its capability for pharmaceutical testing. From human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCM) embedded in collagen-based extracellular matrix hydrogel, we engineered a three-dimensional (3D) electro-mechanically coupled, fluid-ejecting miniature human ventricle-like cardiac organoid chamber (hvCOC). Structural characterization showed organized sarcomeres with myofibrillar microstructures. Transcript and RNA-seq analyses revealed upregulation of key Ca2+-handling, ion channel, and cardiac-specific proteins in hvCOC compared to lower-order 2D and 3D cultures of the same constituent cells. Clinically-important, physiologically complex contractile parameters such as ejection fraction, developed pressure, and stroke work, as well as electrophysiological properties including action potential and conduction velocity were measured: hvCOC displayed key molecular and physiological characteristics of the native ventricle, and showed expected mechanical and electrophysiological responses to a range of pharmacological interventions (including positive and negative inotropes). We conclude that such “human-heart-in-a-jar” technology could facilitate the drug discovery process by providing human-specific preclinical data during early stage drug development.
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影响因子：
5.5
作者：
BASS, BG;CIULLA, EM;VANBAAL, S
通讯作者：
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影响因子：
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作者：
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