Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes

Raniga, Kavita; Nasir, Aishah; Vo, Nguyen T.N.; Vaidyanathan, Ravi; Dickerson, Sarah; Hilcove, Simon; Mosqueira, Diogo; Mirams, Gary R.; Clements, Peter; Hicks, Ryan; Pointon, Amy; Stebbeds, Will; Francis, Jo; Denning, Chris

doi:10.1016/j.stem.2024.01.007

Cited by 5 publications

References 160 publications

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Cardiomyocyte proliferation and regeneration in congenital heart disease

Liang,

He,

Wang

2024

Pediatric Discovery

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Despite advances in prenatal screening and a notable decrease in mortality rates, congenital heart disease (CHD) remains the most prevalent congenital disorder in newborns globally. Current therapeutic surgical approaches face challenges due to the significant rise in complications and disabilities. Emerging cardiac regenerative therapies offer promising adjuncts for CHD treatment. One novel avenue involves investigating methods to stimulate cardiomyocyte proliferation. However, the mechanism of altered cardiomyocyte proliferation in CHD is not fully understood, and there are few feasible approaches to stimulate cardiomyocyte cell cycling for optimal healing in CHD patients. In this review, we explore recent progress in understanding genetic and epigenetic mechanisms underlying defective cardiomyocyte proliferation in CHD from development through birth. Targeting cell cycle pathways shows promise for enhancing cardiomyocyte cytokinesis, division, and regeneration to repair heart defects. Advancements in human disease modeling techniques, clustered regularly interspaced short palindromic repeats ‐based genome and epigenome editing, and next‐generation sequencing technologies will expedite the exploration of abnormal machinery governing cardiomyocyte differentiation, proliferation, and maturation across diverse genetic backgrounds of CHD. Ongoing studies on screening drugs that regulate cell cycling are poised to translate this nascent technology of enhancing cardiomyocyte proliferation into a new therapeutic paradigm for CHD surgical interventions.

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Cardiomyocyte proliferation and regeneration in congenital heart disease

Liang,

He,

Wang

2024

Pediatric Discovery

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Anti-Schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis

Itoh,

Nakahara,

Takashino

et al. 2024

RSC Med. Chem.

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Industrialization of three-dimensional hiPSC-cardiac microtissues for high-throughput cardiac safety and drug discovery screening

de Korte,

Johnson,

Kosmidis

et al. 2024

Preprint

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Current cardiac cell models for drug screening often face a trade-off between cellular maturity and achieving high throughput. While three-dimensional human induced pluripotent stem cell-based heart models typically exhibit more adult-like features, their application is hindered by the need for large cell numbers or complex equipment. Here, we developed cost-effective methods to scale up production of three-dimensional cardiac microtissues (cMTs) containing three cardiac cell types, and assess calcium transients and action potential metrics for high-throughput screening (HTS). Automating the procedure revealed reproducible drug responsiveness and predictive accuracy in a reference compound screen. Furthermore, an arrhythmic phenotype was reliably triggered in cMTs containing cardiomyocytes with a RYR2 mutation. A screen of FDA-approved drugs identified 17 drugs that rescued the arrhythmic phenotype. Our findings underscore the scalability of cMTs and their utility in disease modelling and HTS. The advanced "technology-readiness-level" of cMTs supports their regulatory uptake and acceptance within the pharmaceutical industry.

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Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes

Cited by 5 publications

References 160 publications

Cardiomyocyte proliferation and regeneration in congenital heart disease

Cardiomyocyte proliferation and regeneration in congenital heart disease

Anti-Schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis

Industrialization of three-dimensional hiPSC-cardiac microtissues for high-throughput cardiac safety and drug discovery screening

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