Comprehensive promotion of iPSC-CM maturation by integrating metabolic medium with nanopatterning and electrostimulation

Wener Li, Xiaojing Luo, Anna Strano, Shakthi Arun, Oliver Gamm, Mareike S. Poetsch, Marcel Hasse, Robert-Patrick Steiner, Konstanze Fischer, Jessie Pöche, Ying Ulbricht, Mathias Lesche, Giulia Trimaglio, Ali El-Armouche, Andreas Dahl, Peter Mirtschink, Kaomei Guan () and Mario Schubert ()
Additional contact information
Wener Li: Technische Universität Dresden
Xiaojing Luo: Technische Universität Dresden
Anna Strano: Technische Universität Dresden
Shakthi Arun: Technische Universität Dresden
Oliver Gamm: Technische Universität Dresden
Mareike S. Poetsch: Technische Universität Dresden
Marcel Hasse: Technische Universität Dresden
Robert-Patrick Steiner: Technische Universität Dresden
Konstanze Fischer: Technische Universität Dresden
Jessie Pöche: Technische Universität Dresden
Ying Ulbricht: Technische Universität Dresden
Mathias Lesche: Technische Universität Dresden
Giulia Trimaglio: University Hospital Dresden
Ali El-Armouche: Technische Universität Dresden
Andreas Dahl: Technische Universität Dresden
Peter Mirtschink: University Hospital Dresden
Kaomei Guan: Technische Universität Dresden
Mario Schubert: Technische Universität Dresden

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract The immaturity of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a major limitation for their use in drug screening to identify pro-arrhythmogenic or cardiotoxic molecules. Here, we demonstrate an approach that combines lipid-enriched maturation medium with a high concentration of calcium, nanopatterning of culture surfaces and electrostimulation to generate iPSC-CMs with advanced electrophysiological, structural and metabolic phenotypes. Systematic testing reveals that electrostimulation is the key driver of enhanced mitochondrial development and metabolic maturation and improved electrophysiological properties of iPSC-CMs. Increased calcium concentration strongly promotes electrophysiological maturation, while nanopatterning primarily facilitates sarcomere organisation with minor effect on electrophysiological properties. Transcriptome analysis reveals that activation of HMCES and TFAM targets contributes to mitochondrial development, whereas downregulation of MAPK/PI3K and SRF targets is associated with iPSC-CM polyploidy. These findings provide mechanistic insights into iPSC-CM maturation, paving the way for pharmacological responses that more closely resemble those of adult CMs.

Date: 2025
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DOI: 10.1038/s41467-025-58044-6

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