Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes

Garay, Bayardo I.; Givens, Sophie; Abreu, Phablo; Liu, Man; Yücel, Doğacan; Baik, June; Stanis, Noah; Rothermel, Taylor M.; Magli, Alessandro; Abrahante, Juan; Goloviznina, Natalya A.; Soliman, Hossam A.N.; Dhoke, Neha R.; Kyba, Michael; Alford, Patrick W.; Dudley, Samuel C.; Berlo, Jop H. van; Ogle, Brenda M.; Perlingeiro, Rita

doi:10.1016/j.stemcr.2022.07.003

Cited by 24 publications

(24 citation statements)

References 38 publications

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“…Following this, one approach to increase the maturation of hESC/hiPSC‐CM is to culture them for a long time. Accordingly, hiPSC‐CM show increased cell size and changes in sarcomere organization after 60 days of culture 131 . Longer period promotes increased cell size, cell elongation, better myofibril organization, and improvement of electrophysiological properties and calcium handling 65 .…”

Section: Hesc/hipsc‐cm Maturation Protocolsmentioning

confidence: 99%

“…Accordingly, hiPSC-CM show increased cell size and changes in sarcomere organization after 60 days of culture. 131 Longer period promotes increased cell size, cell elongation, better myofibril organization, and improvement of electrophysiological properties and calcium handling. 65 In accordance, Kamakura et al 133 described that F I G U R E 8 Schematic presentation of different protocols for the maturation of hESC/hiPSC-CM.…”

Section: Long-term Culturementioning

confidence: 99%

“…This phenomenon can limit their potential in cell‐based therapies, disease modelling, or testing drugs' cardiac safety and efficacy. Nonetheless, the embryonic phenotype of hESC/hiPSC‐CM can be used for studies of heart development and cardiomyocyte maturation 99,131 . In recent years, many methods have been established to improve hESC/hiPSC‐CM maturation, including long‐term culture, supplementation with fatty acids, 3D co‐culture with non‐cardiac cells and electrical, and mechanical stimulation 130 (Figure 8) which all mimic the physiological processes occurring in maturating myocardium, its workload, and architecture.…”

Section: Hesc/hipsc‐cm Maturation Protocolsmentioning

confidence: 99%

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Adaptation of cardiomyogenesis to the generation and maturation of cardiomyocytes from human pluripotent stem cells

et al. 2022

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The advent of methods for efficient generation and cardiac differentiation of pluripotent stem cells opened new avenues for disease modelling, drug testing, and cell therapies of the heart. However, cardiomyocytes (CM) obtained from such cells demonstrate an immature, foetal‐like phenotype that involves spontaneous contractions, irregular morphology, expression of embryonic isoforms of sarcomere components, and low level of ion channels. These and other features may affect cellular response to putative therapeutic compounds and the efficient integration into the host myocardium after in vivo delivery. Therefore, novel strategies to increase the maturity of pluripotent stem cell‐derived CM are of utmost importance. Several approaches have already been developed relying on molecular changes that occur during foetal and postnatal maturation of the heart, its electromechanical activity, and the cellular composition. As a better understanding of these determinants may facilitate the generation of efficient protocols for in vitro acquisition of an adult‐like phenotype by immature CM, this review summarizes the most important molecular factors that govern CM during embryonic development, postnatal changes that trigger heart maturation, as well as protocols that are currently used to generate mature pluripotent stem cell‐derived cardiomyocytes.

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Section: Hesc/hipsc‐cm Maturation Protocolsmentioning

confidence: 99%

Section: Long-term Culturementioning

confidence: 99%

Section: Hesc/hipsc‐cm Maturation Protocolsmentioning

confidence: 99%

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Adaptation of cardiomyogenesis to the generation and maturation of cardiomyocytes from human pluripotent stem cells

et al. 2022

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“…[100][101][102] Recently, our group showed that the MAPK and PI3K/AKT signaling pathways are key regulatory modulators of cardiomyocyte maturation and proliferation during development. 103 We combined RNA-seq and ChIP (chromatin immunoprecipitation) sequencing analysis of human cardiac tissue across the life span and showed that the Hippo signaling, Wnt signaling, and MAPK/PI3K/AKT signaling pathways were downregulated postnatally (Figure 2). Several other studies using mammalian systems have also underscored the downregulation of PI3K/AKT signaling with increasing cardiomyocyte maturation, as well as its role in promoting cardiomyocyte proliferation.…”

Section: Mapk and Pi3k/akt Signaling Pathwaymentioning

confidence: 99%

Proliferation and Maturation: Janus and the Art of Cardiac Tissue Engineering

Singh

Yücel

Garay

et al. 2023

Circulation Research

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During cardiac development and morphogenesis, cardiac progenitor cells differentiate into cardiomyocytes that expand in number and size to generate the fully formed heart. Much is known about the factors that regulate initial differentiation of cardiomyocytes, and there is ongoing research to identify how these fetal and immature cardiomyocytes develop into fully functioning, mature cells. Accumulating evidence indicates that maturation limits proliferation and conversely proliferation occurs rarely in cardiomyocytes of the adult myocardium. We term this oppositional interplay the proliferation-maturation dichotomy. Here we review the factors that are involved in this interplay and discuss how a better understanding of the proliferation-maturation dichotomy could advance the utility of human induced pluripotent stem cell–derived cardiomyocytes for modeling in 3-dimensional engineered cardiac tissues to obtain truly adult-level function.

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“…Publications associated with these data sources were manually read to select data sets that 1) had the same cardiomyocyte differentiation (from iPSC) protocol as ours, without further chemical or genetic modification treatment; 2) iPSC-CMs were harvested 30 days or later after differentiation; 3) reported iPSC-CM electrophysiology; 4) have the iPSC-CM bulk-RNA sequencing data generated by Illumina platforms; and 5) the transcript raw count format (required for DeSeq2 gene expression normalization) was available. Two datasets (Zhao et al, 2017;Garay et al, 2022) were selected to be analyzed with A iPSC, V iPSC, A iPSC-CM, and V iPSC-CM RNA sequencing data, which were summarized in Supplementary Table S4. Dataset (Garay et al, 2022) contains iPSC-CM derived from skin tissue after 90 days of differentiation from skin ( S−D90 iPSC-CM) and kidney tissue ( K−D90 iPSC-CM).…”

Section: Collecting Ipsc-cm Bulk-rna Sequencing Reported In the Liter...mentioning

confidence: 99%

Comparative analysis of the cardiomyocyte differentiation potential of induced pluripotent stem cells reprogrammed from human atrial or ventricular fibroblasts

Wang

Nguyen²,

Rosa‐Garrido³

et al. 2023

Front. Bioeng. Biotechnol.

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Background: We had shown that cardiomyocytes (CMs) were more efficiently differentiated from human induced pluripotent stem cells (hiPSCs) when the hiPSCs were reprogrammed from cardiac fibroblasts rather than dermal fibroblasts or blood mononuclear cells. Here, we continued to investigate the relationship between somatic-cell lineage and hiPSC-CM production by comparing the yield and functional properties of CMs differentiated from iPSCs reprogrammed from human atrial or ventricular cardiac fibroblasts (AiPSC or ViPSC, respectively).Methods: Atrial and ventricular heart tissues were obtained from the same patient, reprogrammed into AiPSCs or ViPSCs, and then differentiated into CMs (AiPSC-CMs or ViPSC-CMs, respectively) via established protocols.Results: The time-course of expression for pluripotency genes (OCT4, NANOG, and SOX2), the early mesodermal marker Brachyury, the cardiac mesodermal markers MESP1 and Gata4, and the cardiovascular progenitor-cell transcription factor NKX2.5 were broadly similar in AiPSC-CMs and ViPSC-CMs during the differentiation protocol. Flow-cytometry analyses of cardiac troponin T expression also indicated that purity of the two differentiated hiPSC-CM populations (AiPSC-CMs: 88.23% ± 4.69%, ViPSC-CMs: 90.25% ± 4.99%) was equivalent. While the field-potential durations were significantly longer in ViPSC-CMs than in AiPSC-CMs, measurements of action potential duration, beat period, spike amplitude, conduction velocity, and peak calcium-transient amplitude did not differ significantly between the two hiPSC-CM populations. Yet, our cardiac-origin iPSC-CM showed higher ADP and conduction velocity than previously reported iPSC-CM derived from non-cardiac tissues. Transcriptomic data comparing iPSC and iPSC-CMs showed similar gene expression profiles between AiPSC-CMs and ViPSC-CMs with significant differences when compared to iPSC-CM derived from other tissues. This analysis also pointed to several genes involved in electrophysiology processes responsible for the physiological differences observed between cardiac and non-cardiac-derived cardiomyocytes.Conclusion:AiPSC and ViPSC were differentiated into CMs with equal efficiency. Detected differences in electrophysiological properties, calcium handling activity, and transcription profiles between cardiac and non-cardiac derived cardiomyocytes demonstrated that 1) tissue of origin matters to generate a better-featured iPSC-CMs, 2) the sublocation within the cardiac tissue has marginal effects on the differentiation process.

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Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes

Cited by 24 publications

References 38 publications

Adaptation of cardiomyogenesis to the generation and maturation of cardiomyocytes from human pluripotent stem cells

Adaptation of cardiomyogenesis to the generation and maturation of cardiomyocytes from human pluripotent stem cells

Proliferation and Maturation: Janus and the Art of Cardiac Tissue Engineering

Comparative analysis of the cardiomyocyte differentiation potential of induced pluripotent stem cells reprogrammed from human atrial or ventricular fibroblasts

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