Derivation of ventrical and atrial cardiomyocytes and maturation using biowires

Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionise drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line, non-invasive, recording of passive tension, active force, contractile dynamics and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.

利用人多能干细胞（human pluripotent stem cells）衍生的心肌细胞开展组织工程研究，有望为药物研发领域带来革命性变革，但这一愿景的实现有赖于攻克心脏房室分型与平台通用性相关的技术局限。本研究报道了一种可规模化制备的组织培养平台，该平台不依赖特定细胞来源，且支持电起搏条件下的药物测试。该塑料基平台可实现被动张力、主动肌力、收缩动力学及钙瞬变（Ca2+ transients）的无创在线记录，同时可对动作电位与传导速度进行终点检测。通过将定向细胞分化与电场调控相结合，本研究构建了具备电生理特征差异的心房与心室组织，这些组织可呈现房室特异性的药物响应与基因表达特征。本研究首次报道了包含明确心房端与心室端的异极性心脏组织的构建，并证实这类组织对5-羟色胺（serotonin）与雷诺嗪（ranolazine）呈现空间限制性的特异性响应。尤为独特的是，经长达8个月的电场调控后，本研究可利用患者来源的细胞构建多基因性左心室肥厚（polygenic left ventricular hypertrophy）模型。