Integrated transcriptomic and regulatory network analyses identify microRNA-200c as a novel repressor of human pluripotent stem cell-derived cardiomyocyte differentiation and maturation

Poon, Ellen; Hao, Baixia; Guan, Daogang; Plewczynski, Dariusz; Lü, Jun; Yang, Yong; Wu, Binbin; Wu, Stanley Chun-Ming; Webb, Sarah; Liang, Yan; Miller, Andrew L.; Yao, Xiaoqiang; Wang, Junwen; Yan, Bin; Boheler, Kenneth R.

doi:10.1093/cvr/cvy019

Cited by 48 publications

(33 citation statements)

References 38 publications

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“…As mentioned above, the capacity of endothelial cells to induce multiple facets of mouse ESC-CM maturation led to the discovery that co-culture induces the expression of multiple miRNAs in cardiomyocytes and that an miRNA cocktail (comprising miR-125b, miR-199a, miR-221 and miR-222) is sufficient to increase cell size and binucleation, make resting membrane potential more negative, increase action potential amplitude and upregulate GJA1 and KCNJ2 expression in cardiomyocytes 144 . Gene regulatory analysis of cardiomyocyte differentiation indicates a negative correlation between miR-200c levels (downregulated with differentiation) and transcription factors involved in cardiac development 196 . miR-200c overexpression in hESC-CMs decreased the expression of genes related to calcium handling and ion channels compared with control cells, which was confirmed functionally by calcium transient measurements 196 .…”

Section: Non-coding Rnas and Epigeneticsmentioning

confidence: 99%

“…Gene regulatory analysis of cardiomyocyte differentiation indicates a negative correlation between miR-200c levels (downregulated with differentiation) and transcription factors involved in cardiac development 196 . miR-200c overexpression in hESC-CMs decreased the expression of genes related to calcium handling and ion channels compared with control cells, which was confirmed functionally by calcium transient measurements 196 . Like SRF, these RNAs have developmental stage-specific functions.…”

Section: Non-coding Rnas and Epigeneticsmentioning

confidence: 99%

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Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

et al. 2020

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Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived cardiomyocytes can be generated routinely with high yield and purity for disease research and drug development, and these cells are now gradually entering the clinical research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is the immature state of these cardiomyocytes. In this Review, we describe the structural and functional properties of cardiomyocytes and present the current approaches to mature PSC-derived cardiomyocytes. To date, the greatest success in maturation of PSC-derived cardiomyocytes has been with transplantation into the heart in animal models and the engineering of 3D heart tissues with electromechanical conditioning. In conventional 2D cell culture, biophysical stimuli such as mechanical loading, electrical stimulation and nanotopology cues all induce substantial maturation, particularly of the contractile cytoskeleton. Metabolism has emerged as a potent means to control maturation with unexpected effects on electrical and mechanical function. Different interventions induce distinct facets of maturation, suggesting that activating multiple signalling networks might lead to increased maturation. Despite considerable progress, we are still far from being able to generate PSC-derived cardiomyocytes with adult-like phenotypes in vitro. Future progress will come from identifying the developmental drivers of maturation and leveraging them to create more mature cardiomyocytes for research and regenerative medicine.

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Section: Non-coding Rnas and Epigeneticsmentioning

confidence: 99%

Section: Non-coding Rnas and Epigeneticsmentioning

confidence: 99%

Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

et al. 2020

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“…Poon et al recently described the importance of miR-200c using ES cells, denoting GATA4, TBX5 , and SRF to be its targets [ 36 ]. They noted that knockouts in ES cells altered Ca + , Na + , and K + ion channels ( CACNA1C, KCNJ2 , and SCN5A ), increasing contractility [ 45 ].…”

Section: Mirnas In Cardiomyocytesmentioning

confidence: 99%

A MicroRNA Perspective on Cardiovascular Development and Diseases: An Update

Islas

Moreno-Cuevas

2018

IJMS

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In this review, we summarize the latest research pertaining to MicroRNAs (miRs) related to cardiovascular diseases. In today’s molecular age, the key clinical aspects of diagnosing and treating these type of diseases are crucial, and miRs play an important role. Therefore, we have made a thorough analysis discussing the most important candidate protagonists of many pathways relating to such conditions as atherosclerosis, heart failure, myocardial infarction, and congenital heart disorders. We approach miRs initially from the fundamental molecular aspects and look at their role in developmental pathways, as well as regulatory mechanisms dysregulated under specific cardiovascular conditions. By doing so, we can better understand their functional roles. Next, we look at therapeutic aspects, including delivery and inhibition techniques. We conclude that a personal approach for treatment is paramount, and so understanding miRs is strategic for cardiovascular health.

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“…J Physiol 598.14 transcriptomic analysis has been used to: elucidate stage-specific regulatory networks guiding cardiac development and maturation ; identify nucleosome and histone-modifying genes in maturation (van den Berg et al 2015); identify the role of Let-7 family of microRNAs in guiding CM maturation through metabolic switch (Kuppusamy et al 2015); and identify miR-200c as a regulator of mature ion channel expression and calcium handling (Poon et al 2018). In concert with chromatin immunoprecipitation-sequencing (ChIP-seq), transcriptomic analyses have also been used to develop a stronger understanding of epigenetic dynamics of maturation (Sim et al 2015;Gilsbach et al 2018).…”

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confidence: 99%

Regulation of cardiomyocyte maturation during critical perinatal window

Kannan

Kwon

2019

The Journal of Physiology

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A primary limitation in the use of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) for both patient health and scientific investigation is the failure of these cells to achieve full functional maturity. In vivo, cardiomyocytes undergo numerous adaptive structural, functional and metabolic changes during maturation. By contrast, PSC-CMs fail to fully undergo these developmental processes, instead remaining arrested at an embryonic stage of maturation. There is thus a significant need to understand the biological processes underlying proper CM maturation in vivo. Here, we discuss what is known regarding the initiation and coordination of CM maturation. We postulate that there is a critical perinatal window, ranging from embryonic day 18.5 to postnatal day 14 in mice, in which the maturation process is exquisitely sensitive to perturbation. While the initiation mechanisms of this process are unknown, it is increasingly clear that maturation proceeds through interconnected regulatory circuits that feed into one another to coordinate concomitant structural, functional and metabolic CM maturation. We highlight PGC1α, SRF and the MEF2 family as transcription factors that may potentially mediate this cross-talk. We lastly discuss several emerging technologies that will facilitate future studies into the mechanisms of CM maturation. Further study will not only produce a better understanding of its key processes, but provide practical insights into developing a robust strategy to produce mature PSC-CMs. Abstract figure legendHere, we postulate that there is a critical window, ranging from embryonic day 18.5 to postnatal day 14 in mice, in which interconnected regulatory circuits enable coordinated, concomitant structural, functional and metabolic cardiomyocyte maturation.

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Integrated transcriptomic and regulatory network analyses identify microRNA-200c as a novel repressor of human pluripotent stem cell-derived cardiomyocyte differentiation and maturation

Cited by 48 publications

References 38 publications

Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

A MicroRNA Perspective on Cardiovascular Development and Diseases: An Update

Regulation of cardiomyocyte maturation during critical perinatal window

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