Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Center for Quantitative Biology and Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China.
Commun Biol. 2020 Mar 13;3(1):122. doi: 10.1038/s42003-020-0853-0.
Directed differentiation methods allow acquisition of high-purity cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs); however, their immaturity characteristic limits their application for drug screening and regenerative therapy. The rapid electrical pacing of cardiomyocytes has been used for efficiently promoting the maturation of cardiomyocytes, here we describe a simple device in modified culture plate on which hiPSC-derived cardiomyocytes can form three-dimensional self-organized tissue rings (SOTRs). Using calcium imaging, we show that within the ring, reentrant waves (ReWs) of action potential spontaneously originated and ran robustly at a frequency up to 4 Hz. After 2 weeks, SOTRs with ReWs show higher maturation including structural organization, increased cardiac-specific gene expression, enhanced Ca-handling properties, an increased oxygen-consumption rate, and enhanced contractile force. We subsequently use a mathematical model to interpret the origination, propagation, and long-term behavior of the ReWs within the SOTRs.
定向分化方法可获得高纯度的人诱导多能干细胞（hiPSC）分化的心肌细胞；然而，其不成熟的特性限制了它们在药物筛选和再生治疗中的应用。心肌细胞的快速电起搏已被用于有效促进心肌细胞的成熟，在此我们描述了一种在改良培养板上的简单装置，其上 hiPSC 衍生的心肌细胞可形成三维自组织组织环（SOTR）。通过钙成像，我们显示在环内，动作电位的折返波（ReW）自发起源，并以高达 4 Hz 的频率稳健运行。2 周后，具有 ReW 的 SOTR 表现出更高的成熟度，包括结构组织、增加的心脏特异性基因表达、增强的钙处理特性、增加的耗氧量和增强的收缩力。随后，我们使用数学模型来解释 SOTR 内 ReW 的起源、传播和长期行为。
