Membrane remodelling triggers maturation of excitation–contraction coupling in 3D-shaped human-induced pluripotent stem cell-derived cardiomyocytes
Fatemeh Kermani, Matías Mosqueira, K. Peters, Enrico Domenico Lemma, Kleopatra Rapti, Dirk Grimm, Martin Bastmeyer, Magdalena Laugsch, Markus Hecker, Nina D. Ullrich
Abstract
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 Ca 2+ -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 Ca 2+ channels critical for EC coupling in close proximity, the L-type Ca 2+ channel at the sarcolemma and the ryanodine receptor at the sarcoplasmic reticulum. Consequently, the Ca 2+ -dependent functional interaction of these channels becomes more efficient, leading to improved spatio-temporal synchronisation of Ca 2+ 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.