Cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) are functionally immature, but this is improved by incorporation into engineered tissues or forced contraction. Here, we showed that tri-cellular combinations of hiPSC-derived CMs, cardiac fibroblasts (CFs), and cardiac endothelial cells also enhance maturation in easily constructed, scaffold-free, three-dimensional microtissues (MTs). hiPSC-CMs in MTs with CFs showed improved sarcomeric structures with T-tubules, enhanced contractility, and mitochondrial respiration and were electrophysiologically more mature than MTs without CFs. Interactions mediating maturation included coupling between hiPSC-CMs and CFs through connexin 43 (CX43) gap junctions and increased intracellular cyclic AMP (cAMP). Scaled production of thousands of hiPSC-MTs was highly reproducible across lines and differentiated cell batches. MTs containing healthy-control hiPSC-CMs but hiPSC-CFs from patients with arrhythmogenic cardiomyopathy strikingly recapitulated features of the disease. Our MT model is thus a simple and versatile platform for modeling multicellular cardiac diseases that will facilitate industry and academic engagement in high-throughput molecular screening.

Human-iPSC-Derived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart Disease / E. Giacomelli, V. Meraviglia, G. Campostrini, A. Cochrane, X. Cao, R.W.J. van Helden, A. Krotenberg Garcia, M. Mircea, S. Kostidis, R.P. Davis, B.J. van Meer, C.R. Jost, A.J. Koster, H. Mei, D.G. Miguez, A.A. Mulder, M. Ledesma-Terron, G. Pompilio, L. Sala, D.C.F. Salvatori, R.C. Slieker, E. Sommariva, A.A.F. de Vries, M. Giera, S. Semrau, L.G.J. Tertoolen, V.V. Orlova, M. Bellin, C.L. Mummery. - In: CELL STEM CELL. - ISSN 1934-5909. - 26:6(2020 Jun 04), pp. 862-879.e11. [10.1016/j.stem.2020.05.004]

Human-iPSC-Derived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart Disease

G. Campostrini;G. Pompilio;
2020-06-04

Abstract

Cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) are functionally immature, but this is improved by incorporation into engineered tissues or forced contraction. Here, we showed that tri-cellular combinations of hiPSC-derived CMs, cardiac fibroblasts (CFs), and cardiac endothelial cells also enhance maturation in easily constructed, scaffold-free, three-dimensional microtissues (MTs). hiPSC-CMs in MTs with CFs showed improved sarcomeric structures with T-tubules, enhanced contractility, and mitochondrial respiration and were electrophysiologically more mature than MTs without CFs. Interactions mediating maturation included coupling between hiPSC-CMs and CFs through connexin 43 (CX43) gap junctions and increased intracellular cyclic AMP (cAMP). Scaled production of thousands of hiPSC-MTs was highly reproducible across lines and differentiated cell batches. MTs containing healthy-control hiPSC-CMs but hiPSC-CFs from patients with arrhythmogenic cardiomyopathy strikingly recapitulated features of the disease. Our MT model is thus a simple and versatile platform for modeling multicellular cardiac diseases that will facilitate industry and academic engagement in high-throughput molecular screening.
arrhythmogenic cardiomyopathy; cAMP; cardiac disease model; cardiac microtissue; cardiomyocyte maturation; cell-cell interaction; cyclic AMP; gap junction; human-induced-pluripotent-stem-cell-derived cardiac fibroblasts; human-induced-pluripotent-stem-cell-derived cardiomyocytes
Settore MED/11 - Malattie dell'Apparato Cardiovascolare
Settore MED/23 - Chirurgia Cardiaca
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/739778
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