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<p>Maturation of human pluripotent stem (hPS) cell-derived cardiomyocytes is critical for their use as a model system. Here we mimic human heart maturation pathways in the setting of hPS cell-derived cardiac organoids (hCOs). Specifically, transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor enhanced cardiomyocyte maturation, inducing expression of mature sarcomeric and oxidative phosphorylation proteins, and increasing metabolic capacity. hCOs generated using the directed maturation protocol (DM-hCOs) recapitulate cardiac drug responses and, when derived from calsequestrin 2 (<i>CASQ2</i>) and ryanodine receptor 2 (<i>RYR2</i>) mutant hPS cells exhibit a pro-arrhythmia phenotype. These DM-hCOs also comprise multiple cell types, which we characterize and benchmark to the human heart. Modeling of cardiomyopathy caused by a desmoplakin (<i>DSP</i>) mutation resulted in fibrosis and cardiac dysfunction and led to identifying the bromodomain and extra-terminal inhibitor INCB054329 as a drug mitigating the desmoplakin-related functional defect. These findings establish DM-hCOs as a versatile platform for applications in cardiac biology, disease and drug screening.</p>

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Maturation of human cardiac organoids enables complex disease modeling and drug discovery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月25日

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  • Mark W. Pocock,
  • Janice D. Reid,
  • Harley R. Robinson,
  • Natalie Charitakis,
  • James R. Krycer,
  • Simon R. Foster,
  • Rebecca L. Fitzsimmons,
  • Mary Lor,
  • Lynn A. C. Devilée,
  • Christopher A. P. Batho,
  • Natasha Tuano,
  • Sara E. Howden,
  • Katerina Vlahos,
  • Kevin I. Watt,
  • Adam T. Piers,
  • Kaitlyn Bibby,
  • James W. McNamara,
  • Rebecca Sutton,
  • Valerii Iaprintsev,
  • Jacob Mathew,
  • Holly K. Voges,
  • Patrick R. J. Fortuna,
  • Sebastian Bass-Stringer,
  • Celine Vivien,
  • James Rae,
  • Robert G. Parton,
  • Anthony B. Firulli,
  • Leszek Lisowski,
  • Hannah Huckstep,
  • Sean J. Humphrey,
  • Sean Lal,
  • Igor E. Konstantinov,
  • Robert G. Weintraub,
  • David A. Elliott,
  • Mirana Ramialison,
  • Enzo R. Porrello,
  • Richard J. Mills,
  • James E. Hudson

摘要

Maturation of human pluripotent stem (hPS) cell-derived cardiomyocytes is critical for their use as a model system. Here we mimic human heart maturation pathways in the setting of hPS cell-derived cardiac organoids (hCOs). Specifically, transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor enhanced cardiomyocyte maturation, inducing expression of mature sarcomeric and oxidative phosphorylation proteins, and increasing metabolic capacity. hCOs generated using the directed maturation protocol (DM-hCOs) recapitulate cardiac drug responses and, when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype. These DM-hCOs also comprise multiple cell types, which we characterize and benchmark to the human heart. Modeling of cardiomyopathy caused by a desmoplakin (DSP) mutation resulted in fibrosis and cardiac dysfunction and led to identifying the bromodomain and extra-terminal inhibitor INCB054329 as a drug mitigating the desmoplakin-related functional defect. These findings establish DM-hCOs as a versatile platform for applications in cardiac biology, disease and drug screening.