Learn from Your Elders: Developmental Biology Lessons to Guide Maturation of Stem Cell-Derived Cardiomyocytes

Abstract

Human pluripotent stem cells (hPSCs) offer a multifaceted platform to study cardiac developmental biology, understand disease mechanisms, and develop novel therapies. Remarkable progress over the last two decades has led to methods to obtain highly pure hPSC-derived cardiomyocytes (hPSC-CMs) with reasonable ease and scalability. Nevertheless, a major bottleneck for the translational application of hPSC-CMs is their immature phenotype, resembling that of early fetal cardiomyocytes. Overall, bona fide maturation of hPSC-CMs represents one of the most significant goals facing the field today. Developmental biology studies have been pivotal in understanding the mechanisms to differentiate hPSC-CMs. Similarly, evaluation of developmental cues such as electrical and mechanical activities or neurohormonal and metabolic stimulations revealed the importance of these pathways in cardiomyocyte physiological maturation. Those signals cooperate and dictate the size and the performance of the developing heart. Likewise, this orchestra of stimuli is important in promoting hPSC-CM maturation, as demonstrated by current in vitro maturation approaches. Different shades of adult-like phenotype are achieved by prolonging the time in culture, electromechanical stimulation, patterned substrates, microRNA manipulation, neurohormonal or metabolic stimulation, and generation of human-engineered heart tissue (hEHT). However, mirroring this extremely dynamic environment is challenging, and reproducibility and scalability of these approaches represent the major obstacles for an efficient production of mature hPSC-CMs. For this reason, understanding the pattern behind the mechanisms elicited during the late gestational and early postnatal stages not only will provide new insights into postnatal development but also potentially offer new scalable and efficient approaches to mature hPSC-CMs.

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Acknowledgements

We thank all the current and past members of the Murry lab and of the UW Medicine Heart Regeneration Program for the insightful discussions.

Funding

AB holds an EMBO Long-Term Fellowship (ALTF 448–2017). CEM is supported by the National Institute of Health grants R01HL128362, R01H128368, R01HL141570, R01HL141868, U01HL100405, and a grant from the Fondation Leducq Transatlantic Network of Excellence.

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Correspondence to Charles E. Murry.

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CEM is a scientific founder and equity holder in Cytocardia.

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Marchianò, S., Bertero, A. & Murry, C.E. Learn from Your Elders: Developmental Biology Lessons to Guide Maturation of Stem Cell-Derived Cardiomyocytes. Pediatr Cardiol 40, 1367–1387 (2019). https://doi.org/10.1007/s00246-019-02165-5

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Keywords

  • Postnatal cardiac development
  • Human embryonic stem cells
  • Human induced pluripotent stem cells
  • Cardiomyocyte maturation