An Epigenetic Roadmap for Cardiomyocyte Differentiation

Parmacek, Michael S.; Epstein, Jonathan A.

doi:10.1161/circresaha.113.301134

Cited by 4 publications

(5 citation statements)

References 9 publications

(9 reference statements)

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“…Two groups, Paige et al (2012) (hESCs-to-CMs) and Wamstad et al (2012) (mESCs-to-CMs) have profiled global histone modifications and gene expression in prior studies of CM differentiation. However, cellular heterogeneity, including final CM preparations that were ~ 25–30% cTnT(−) cells, significantly confounded epigenomic results ( Parmacek and Epstein, 2013 ). Here, we can estimate that at minimum, 26% of D3 cells would be ROR2(−), 30% of D4 cells ROR2(+)/PDGFRα(−), and 21% of D31 cells (final CM time point) cTnT(−) ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Mapping Human Pluripotent-to-Cardiomyocyte Differentiation: Methylomes, Transcriptomes, and Exon DNA Methylation “Memories”

et al. 2016

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The directed differentiation of human cardiomyocytes (CMs) from pluripotent cells provides an invaluable model for understanding mechanisms of cell fate determination and offers considerable promise in cardiac regenerative medicine. Here, we utilize a human embryonic stem cell suspension bank, produced according to a good manufacturing practice, to generate CMs using a fully defined and small molecule-based differentiation strategy. Primitive and cardiac mesoderm purification was used to remove non-committing and multi-lineage populations and this significantly aided the identification of key transcription factors, lncRNAs, and essential signaling pathways that define cardiomyogenesis. Global methylation profiles reflect CM development and we report on CM exon DNA methylation “memories” persisting beyond transcription repression and marking the expression history of numerous developmentally regulated genes, especially transcription factors.

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Section: Discussionmentioning

confidence: 99%

Mapping Human Pluripotent-to-Cardiomyocyte Differentiation: Methylomes, Transcriptomes, and Exon DNA Methylation “Memories”

et al. 2016

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“…As aforementioned, previous studies have been used to obtain CM-like cells from ES cells (Chen et al, 2008;Dambrot et al, 2011;Kattman et al, 2011;Klattenhoff et al, 2013;Parmacek and Epstein, 2013). As indicated in Figure 1, the designed threestep differentiation protocol used is depicted.…”

Section: Resultsmentioning

confidence: 99%

“…Considerable effort has been placed into promoting differentiation of these cells into the CM cell lineage (Wobus et al, 1997;Guan et al, 1999;Fehling et al, 2003;Yuasa et al, 2005;Kattman et al, 2006Kattman et al, , 2011Chen et al, 2008;Ding et al, 2008;Dambrot et al, 2011;Sun et al, 2011;Wang et al, 2011;Flaherty et al, 2012;Jiang et al, 2012;Wamstad et al, 2012;Parmacek and Epstein, 2013;Correia et al, 2014;Engels et al, 2014); (Table 1). Most of the techniques used are based on the embryoid body formation step that makes CM differentiation yield highly variable and causes cell loss by trypsinisation.…”

Section: Introductionmentioning

confidence: 99%

Cardiomyocyte differentiation from mouse embryonic stem cells using a simple and defined protocol

Kokkinopoulos

Ishida

Saba

et al. 2015

Developmental Dynamics

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Background: Embryonic stem (ES) cells are pluripotent cells with the ability to differentiate to any cell type of the resident organism. In recent years, significant advances have been made in using these cells to obtain large numbers of cardiomyocyte (CM) -like cells for scientific research and clinical application. A vast number of protocols have emerged describing differentiation methods without the use of animal serum or extracts restrictive for use in a human clinical setting. These techniques follow a complicated procedure, which although successful, show a relatively varied yield among cell batches. Results: We have designed a three-step differentiation protocol using defined reagents and a monolayer culture without feeder cells, avoiding embryoid body formation and multiple trypsin treatment, in which beating foci appeared as early as day 6 in in vitro differentiating conditions. Our results show a high yield of CM reaching approximately 60% of the differentiated cells after 13 days in vitro.

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“…Histone 3 lysine 27 (H3K27) trimethylation (H3K27m3) is characteristic of inactive/repressive chromatin, whereas H3K4 trimethylation (H3K4me3) is characteristic of active promoters. 48 Pluripotent ESCs have been shown to have H3K4me3 and H3K27me3 located together at promoter and enhancer regions of poised key developmental genes. 49 During cardiac lineage formation, dynamic chromatin modifications, such as the acquisition of H3K4me3 and H3K27me3 by various transcription factors, have been identified.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Development in the Presence of Cadmium: An in Vitro Study Using Human Embryonic Stem Cells and Cardiac Organoids

Chen

Luz

et al. 2022

Environ Health Perspect

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Background: Exposure to cadmium (Cd) is associated with cardiovascular diseases. Maternal Cd exposure is a significant risk factor for congenital heart disease. However, mechanisms of Cd on developmental cardiotoxicity are not well defined. Objectives: We evaluated the effects of Cd on the different stages (mesoderm, cardiac induction, cardiac function) of cardiac development using an early embryo development in vitro model and two- or three-dimensional (2- or 3D) cardiomyocyte and cardiac organoid formation models mimicking early cardiac development. Methods: Embryonic stem cells (ESCs) form 3D aggregates, called embryoid bodies, that recapitulate events involved with early embryogenesis (e.g., germ layer formation). This model was used for early germ layer formation and signaling pathway identification. The 2D cardiomyocyte differentiation from the human ESCs model was used to explore the effects of Cd exposure on cardiomyocyte formation and to model mesoderm differentiation and cardiac induction, allowing us to explore different developmental windows of Cd toxicity. The 3D cardiac organoid model was used in evaluating the effects of Cd exposure on contractility and cardiac development. Results: Cd ( ; ) lowered the differentiation of embryoid bodies to mesoderm via suppression of –signaling pathways. During early mesoderm induction, the mesoderm-associated transcription factors MESP1 and EOMES showed a transient up-regulation, which decreased later in the cardiac induction stage. Cd ( ) lowered mesoderm formation and cardiac induction through suppression of the transcription factors and mesoderm marker genes HAND1 , SNAI2 , HOPX , and the cardiac-specific genes NKX2 -5, GATA4 , troponin T, and . In addition, Cd-induced histone modifications for both gene activation (H3K4me3) and repression (H3K27me3), which play vital roles in regulating mesoderm commitment markers. The effects of Cd inhibition on cardiomyocyte differentiation were confirmed in 3D cardiac organoids. Discussion: In conclusion, using a human ESC-derived 2D/3D in vitro differentiation model system and cardiac organoids, we demonstrated that low-dose Cd suppressed mesoderm formation through mesoderm gene histone modification, thus inhibiting cardiomyocyte differentiation and cardiac induction. The studies provide valuable insights into cellular events and molecular mechanisms associated with Cd-induced congenital heart disease. https://doi.org/10.1289/EHP11208

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An Epigenetic Roadmap for Cardiomyocyte Differentiation

Cited by 4 publications

References 9 publications

Mapping Human Pluripotent-to-Cardiomyocyte Differentiation: Methylomes, Transcriptomes, and Exon DNA Methylation “Memories”

Mapping Human Pluripotent-to-Cardiomyocyte Differentiation: Methylomes, Transcriptomes, and Exon DNA Methylation “Memories”

Cardiomyocyte differentiation from mouse embryonic stem cells using a simple and defined protocol

Cardiac Development in the Presence of Cadmium: An in Vitro Study Using Human Embryonic Stem Cells and Cardiac Organoids

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