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Abstract：
The prospective use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) for cardiac regenerative medicine strongly depends on the electro-mechanical properties of these cells, especially regarding the Ca2+-dependent excitation-contraction (EC) coupling mechanism. Currently, the immature structural and functional features of hiPSC-CM limit the progression towards clinical applications. Here, we show that a specific microarchitecture is essential for functional maturation of hiPSC-CM. Structural remodelling towards a cuboid cell shape and induction of BIN1, a facilitator of membrane invaginations, lead to transverse (t)-tubule-like structures. This transformation brings two Ca2+ channels critical for EC coupling in close proximity, the L-type Ca2+ channel at the sarcolemma and the ryanodine receptor at the sarcoplasmic reticulum. Consequently, the Ca2+-dependent functional interaction of these channels becomes more efficient, leading to improved spatio-temporal synchronisation of Ca2+ transients and higher EC coupling gain. Thus, functional maturation of hiPSC-cardiomyocytes by optimised cell microarchitecture needs to be considered for future cardiac regenerative approaches.
摘要：
人类诱导的多能干细胞衍生的心肌细胞（hiPSC-CM）在心脏再生医学中的未来用途在很大程度上取决于这些细胞的机电特性。特别是关于Ca2+依赖的激发-收缩(EC)耦合机制。目前,hiPSC-CM不成熟的结构和功能特征限制了其临床应用的进展.这里,我们表明，特定的微结构对于hiPSC-CM的功能成熟至关重要。向长方体细胞形状的结构重塑和BIN1的诱导，BIN1是膜内陷的促进剂，导致横向（t）管状结构。这种转变带来了两个对EC耦合至关重要的Ca2通道，肌膜上的L型Ca2通道和肌浆网上的ryanodine受体。因此,这些通道的Ca2+依赖性功能相互作用变得更有效，导致改进的Ca2+瞬变的时空同步和更高的EC耦合增益。因此，未来的心脏再生方法需要考虑通过优化的细胞微体系结构实现hiPSC心肌细胞的功能成熟。
