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

Author

Listed:
  • 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
    and German Cancer Research Center)

  • 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)

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.

Suggested Citation

  • 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 & Gi, 2025. "Comprehensive promotion of iPSC-CM maturation by integrating metabolic medium with nanopatterning and electrostimulation," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58044-6
    DOI: 10.1038/s41467-025-58044-6
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    References listed on IDEAS

    as
    1. Shunsuke Funakoshi & Ian Fernandes & Olya Mastikhina & Dan Wilkinson & Thinh Tran & Wahiba Dhahri & Amine Mazine & Donghe Yang & Benjamin Burnett & Jeehoon Lee & Stephanie Protze & Gary D. Bader & Sar, 2021. "Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells," Nature Communications, Nature, vol. 12(1), pages 1-23, December.
    2. Yao-Chang Tsan & Samuel J. DePalma & Yan-Ting Zhao & Adela Capilnasiu & Yu-Wei Wu & Brynn Elder & Isabella Panse & Kathryn Ufford & Daniel L. Matera & Sabrina Friedline & Thomas S. O’Leary & Nadab Wub, 2021. "Physiologic biomechanics enhance reproducible contractile development in a stem cell derived cardiac muscle platform," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Kacey Ronaldson-Bouchard & Stephen P. Ma & Keith Yeager & Timothy Chen & LouJin Song & Dario Sirabella & Kumi Morikawa & Diogo Teles & Masayuki Yazawa & Gordana Vunjak-Novakovic, 2018. "Advanced maturation of human cardiac tissue grown from pluripotent stem cells," Nature, Nature, vol. 556(7700), pages 239-243, April.
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