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Nature Reviews. Cardiology Sep 2022Interest in epicardial adipose tissue (EAT) is growing rapidly, and research in this area appeals to a broad, multidisciplinary audience. EAT is unique in its anatomy... (Review)
Review
Interest in epicardial adipose tissue (EAT) is growing rapidly, and research in this area appeals to a broad, multidisciplinary audience. EAT is unique in its anatomy and unobstructed proximity to the heart and has a transcriptome and secretome very different from that of other fat depots. EAT has physiological and pathological properties that vary depending on its location. It can be highly protective for the adjacent myocardium through dynamic brown fat-like thermogenic function and harmful via paracrine or vasocrine secretion of pro-inflammatory and profibrotic cytokines. EAT is a modifiable risk factor that can be assessed with traditional and novel imaging techniques. Coronary and left atrial EAT are involved in the pathogenesis of coronary artery disease and atrial fibrillation, respectively, and it also contributes to the development and progression of heart failure. In addition, EAT might have a role in coronavirus disease 2019 (COVID-19)-related cardiac syndrome. EAT is a reliable potential therapeutic target for drugs with cardiovascular benefits such as glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter 2 inhibitors. This Review provides a comprehensive and up-to-date overview of the role of EAT in cardiovascular disease and highlights the translational nature of EAT research and its applications in contemporary cardiology.
Topics: Adipose Tissue; Atrial Fibrillation; COVID-19; Cardiology; Humans; Pericardium
PubMed: 35296869
DOI: 10.1038/s41569-022-00679-9 -
American Journal of Medical Genetics.... Mar 2020In 2014, an extensive review discussing the major steps of cardiac development focusing on growth, formation of primary and chamber myocardium and the development of the... (Review)
Review
In 2014, an extensive review discussing the major steps of cardiac development focusing on growth, formation of primary and chamber myocardium and the development of the cardiac electrical system, was published. Molecular genetic lineage analyses have since furthered our insight in the developmental origin of the various component parts of the heart, which currently can be unambiguously identified by their unique molecular phenotype. Moreover, genetic, molecular and cell biological analyses have driven insights into the mechanisms underlying the development of the different cardiac components. Here, we build on our previous review and provide an insight into the molecular mechanistic revelations that have forwarded the field of cardiac development. Despite the enormous advances in our knowledge over the last decade, the development of congenital cardiac malformations remains poorly understood. The challenge for the next decade will be to evaluate the different developmental processes using newly developed molecular genetic techniques to further unveil the gene regulatory networks operational during normal and abnormal cardiac development.
Topics: Gene Expression Regulation, Developmental; Gene Regulatory Networks; Heart; Heart Defects, Congenital; Heart Valves; Humans; Pericardium; Phenotype
PubMed: 32048790
DOI: 10.1002/ajmg.c.31778 -
Circulation Research Jul 2022Establishment of the myocardial wall requires proper growth cues from nonmyocardial tissues. During heart development, the epicardium and epicardium-derived cells...
BACKGROUND
Establishment of the myocardial wall requires proper growth cues from nonmyocardial tissues. During heart development, the epicardium and epicardium-derived cells instruct myocardial growth by secreting essential factors including FGF (fibroblast growth factor) 9 and IGF (insulin-like growth factor) 2. However, it is poorly understood how the epicardial secreted factors are regulated, in particular by chromatin modifications for myocardial formation. The current study is to investigate whether and how HDAC (histone deacetylase) 3 in the developing epicardium regulates myocardial growth.
METHODS
Various cellular and mouse models in conjunction with biochemical and molecular tools were employed to study the role of HDAC3 in the developing epicardium.
RESULTS
We deleted in the developing murine epicardium, and mutant hearts showed ventricular myocardial wall hypoplasia with reduction of epicardium-derived cells. The cultured embryonic cardiomyocytes with supernatants from knockout (KO) mouse epicardial cells also showed decreased proliferation. Genome-wide transcriptomic analysis revealed that and were significantly downregulated in KO mouse epicardial cells. We further found that and expression is dependent on HDAC3 deacetylase activity. The supplementation of FGF9 or IGF2 can rescue the myocardial proliferation defects treated by KO supernatant. Mechanistically, we identified that microRNA (miR)-322 and miR-503 were upregulated in KO mouse epicardial cells and epicardial KO hearts. Overexpression of miR-322 or miR-503 repressed FGF9 and IGF2 expression, while knockdown of miR-322 or miR-503 restored FGF9 and IGF2 expression in KO mouse epicardial cells.
CONCLUSIONS
Our findings reveal a critical signaling pathway in which epicardial HDAC3 promotes compact myocardial growth by stimulating FGF9 and IGF2 through repressing miR-322 or miR-503, providing novel insights in elucidating the etiology of congenital heart defects and conceptual strategies to promote myocardial regeneration.
Topics: Animals; Heart; Mice; MicroRNAs; Myocardium; Myocytes, Cardiac; Pericardium; Signal Transduction
PubMed: 35722872
DOI: 10.1161/CIRCRESAHA.122.320785 -
Circulation Jun 2021Arrhythmogenic cardiomyopathy (ACM) manifests with sudden death, arrhythmias, heart failure, apoptosis, and myocardial fibro-adipogenesis. The phenotype typically starts...
BACKGROUND
Arrhythmogenic cardiomyopathy (ACM) manifests with sudden death, arrhythmias, heart failure, apoptosis, and myocardial fibro-adipogenesis. The phenotype typically starts at the epicardium and advances transmurally. Mutations in genes encoding desmosome proteins, including DSP (desmoplakin), are major causes of ACM.
METHODS
To delineate contributions of the epicardium to the pathogenesis of ACM, the allele was conditionally deleted in the epicardial cells in mice upon expression of tamoxifen-inducible Cre from the locus. Wild type (WT) and were crossed to Rosa26 (R26) dual reporter mice to tag the epicardial-derived cells with the EGFP (enhanced green fluorescent protein) reporter protein. Tagged epicardial-derived cells from adult :R26 and : R26 mouse hearts were isolated by fluorescence-activated cell staining and sequenced by single-cell RNA sequencing.
RESULTS
WT1 (Wilms tumor 1) expression was progressively restricted postnatally and was exclusive to the epicardium by postnatal day 21. Expression of was reduced in the epicardial cells but not in cardiac myocytes in the mice. The mice exhibited premature death, cardiac dysfunction, arrhythmias, myocardial fibro-adipogenesis, and apoptosis. Single-cell RNA sequencing of ≈18 000 EGFP-tagged epicardial-derived cells identified genotype-independent clusters of endothelial cells, fibroblasts, epithelial cells, and a very small cluster of cardiac myocytes, which were confirmed on coimmunofluorescence staining of the myocardial sections. Differentially expressed genes between the paired clusters in the 2 genotypes predicted activation of the inflammatory and mitotic pathways-including the TGFβ1 (transforming growth factor β1) and fibroblast growth factors-in the epicardial-derived fibroblast and epithelial clusters, but predicted their suppression in the endothelial cell cluster. The findings were corroborated by analysis of gene expression in the pooled RNA-sequencing data, which identified predominant dysregulation of genes involved in epithelial-mesenchymal transition, and dysregulation of 146 genes encoding the secreted proteins (secretome), including genes in the TGFβ1 pathway. Activation of the TGFβ1 and its colocalization with fibrosis in the :R26 mouse heart was validated by complementary methods.
CONCLUSIONS
Epicardial-derived cardiac fibroblasts and epithelial cells express paracrine factors, including TGFβ1 and fibroblast growth factors, which mediate epithelial-mesenchymal transition, and contribute to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of ACM. The findings uncover contributions of the epicardial-derived cells to the pathogenesis of ACM.
Topics: Animals; Cardiomyopathies; Disease Models, Animal; Humans; Mice; Paracrine Communication; Pericardium; Sequence Analysis, RNA; Single-Cell Analysis; Survival Analysis
PubMed: 33726497
DOI: 10.1161/CIRCULATIONAHA.120.052928 -
Journal of the American College of... May 2018Epicardial adipose tissue has unique properties that distinguish it from other depots of visceral fat. Rather than having distinct boundaries, the epicardium shares an... (Review)
Review
Epicardial adipose tissue has unique properties that distinguish it from other depots of visceral fat. Rather than having distinct boundaries, the epicardium shares an unobstructed microcirculation with the underlying myocardium, and in healthy conditions, produces cytokines that nourish the heart. However, in chronic inflammatory disorders (especially those leading to heart failure with preserved ejection fraction), the epicardium becomes a site of deranged adipogenesis, leading to the secretion of proinflammatory adipokines that can cause atrial and ventricular fibrosis. Accordingly, in patients at risk of heart failure with preserved ejection fraction, drugs that promote the accumulation or inflammation of epicardial adipocytes may lead to heart failure, whereas treatments that ameliorate the proinflammatory characteristics of epicardial fat may reduce the risk of heart failure. These observations suggest that epicardial adipose tissue is a transducer of the adverse effects of systemic inflammation and metabolic disorders on the heart, and thus, represents an important target for therapeutic interventions.
Topics: Adipose Tissue; Humans; Inflammation; Inflammation Mediators; Intra-Abdominal Fat; Myocardium; Obesity; Pericardium; Randomized Controlled Trials as Topic
PubMed: 29773163
DOI: 10.1016/j.jacc.2018.03.509 -
Cold Spring Harbor Perspectives in... Feb 2020The epicardium, the outermost tissue layer that envelops all vertebrate hearts, plays a crucial role in cardiac development and regeneration and has been implicated in... (Review)
Review
The epicardium, the outermost tissue layer that envelops all vertebrate hearts, plays a crucial role in cardiac development and regeneration and has been implicated in potential strategies for cardiac repair. The heterogenous cell population that composes the epicardium originates primarily from a transient embryonic cell cluster known as the proepicardial organ (PE). Characterized by its high cellular plasticity, the epicardium contributes to both heart development and regeneration in two critical ways: as a source of progenitor cells and as a critical signaling hub. Despite this knowledge, there are many unanswered questions in the field of epicardial biology, the resolution of which will advance the understanding of cardiac development and repair. We review current knowledge in cross-species epicardial involvement, specifically in relation to lineage specification and differentiation during cardiac development.
Topics: Animals; Cell Differentiation; Pericardium; Regeneration; Stem Cells
PubMed: 31451510
DOI: 10.1101/cshperspect.a037192 -
Protein & Cell May 2023Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac...
Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac regeneration capacity. Several cell types and signaling pathways have been reported to participate in this process. However, a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable. We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration. We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes, and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration. Furthermore, we identified a regeneration-induced cell (RIC) population in the epicardium-derived cells (EPDC), and demonstrated Angiopoietin 4 (Angpt4) as a specific regulator of heart regeneration. angpt4 expression is specifically and transiently activated in RIC, which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway, and further induces activation of cathepsin K in cardiomyocytes through RA signaling. Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation, while overexpression of angpt4 accelerates regeneration. Furthermore, we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes, and promote cardiac repair in mice after myocardial infarction, indicating that the function of Angpt4 is conserved in mammals. Our study provides a mechanistic understanding of heart regeneration at single-cell precision, identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration, and offers a novel therapeutic target for improved recovery after human heart injuries.
Topics: Humans; Mice; Rats; Cell Proliferation; Heart; Myocardial Infarction; Myocytes, Cardiac; Pericardium; Single-Cell Analysis; Zebrafish; Animals
PubMed: 37155312
DOI: 10.1093/procel/pwac010 -
Nature Reviews. Cardiology Oct 2018After decades of directed research, no effective regenerative therapy is currently available to repair the injured human heart. The epicardium, a layer of mesothelial... (Review)
Review
After decades of directed research, no effective regenerative therapy is currently available to repair the injured human heart. The epicardium, a layer of mesothelial tissue that envelops the heart in all vertebrates, has emerged as a new player in cardiac repair and regeneration. The epicardium is essential for muscle regeneration in the zebrafish model of innate heart regeneration, and the epicardium also participates in fibrotic responses in mammalian hearts. This structure serves as a source of crucial cells, such as vascular smooth muscle cells, pericytes, and fibroblasts, during heart development and repair. The epicardium also secretes factors that are essential for proliferation and survival of cardiomyocytes. In this Review, we describe recent advances in our understanding of the biology of the epicardium and the effect of these findings on the candidacy of this structure as a therapeutic target for heart repair and regeneration.
Topics: Animals; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Survival; Disease Models, Animal; Heart Diseases; Humans; Mice, Transgenic; Organogenesis; Pericardium; Recovery of Function; Regeneration; Regenerative Medicine; Signal Transduction
PubMed: 29950578
DOI: 10.1038/s41569-018-0046-4 -
Nature Biotechnology Dec 2023The epicardium, the mesothelial envelope of the vertebrate heart, is the source of multiple cardiac cell lineages during embryonic development and provides signals that...
The epicardium, the mesothelial envelope of the vertebrate heart, is the source of multiple cardiac cell lineages during embryonic development and provides signals that are essential to myocardial growth and repair. Here we generate self-organizing human pluripotent stem cell-derived epicardioids that display retinoic acid-dependent morphological, molecular and functional patterning of the epicardium and myocardium typical of the left ventricular wall. By combining lineage tracing, single-cell transcriptomics and chromatin accessibility profiling, we describe the specification and differentiation process of different cell lineages in epicardioids and draw comparisons to human fetal development at the transcriptional and morphological levels. We then use epicardioids to investigate the functional cross-talk between cardiac cell types, gaining new insights into the role of IGF2/IGF1R and NRP2 signaling in human cardiogenesis. Finally, we show that epicardioids mimic the multicellular pathogenesis of congenital or stress-induced hypertrophy and fibrotic remodeling. As such, epicardioids offer a unique testing ground of epicardial activity in heart development, disease and regeneration.
Topics: Humans; Pericardium; Heart; Myocardium; Cell Differentiation; Cell Lineage; Biology
PubMed: 37012447
DOI: 10.1038/s41587-023-01718-7 -
Circulation Research Jan 2020The heart is lined by a single layer of mesothelial cells called the epicardium that provides important cellular contributions for embryonic heart formation. The... (Review)
Review
The heart is lined by a single layer of mesothelial cells called the epicardium that provides important cellular contributions for embryonic heart formation. The epicardium harbors a population of progenitor cells that undergo epithelial-to-mesenchymal transition displaying characteristic conversion of planar epithelial cells into multipolar and invasive mesenchymal cells before differentiating into nonmyocyte cardiac lineages, such as vascular smooth muscle cells, pericytes, and fibroblasts. The epicardium is also a source of paracrine cues that are essential for fetal cardiac growth, coronary vessel patterning, and regenerative heart repair. Although the epicardium becomes dormant after birth, cardiac injury reactivates developmental gene programs that stimulate epithelial-to-mesenchymal transition; however, it is not clear how the epicardium contributes to disease progression or repair in the adult. In this review, we will summarize the molecular mechanisms that control epicardium-derived progenitor cell migration, and the functional contributions of the epicardium to heart formation and cardiomyopathy. Future perspectives will be presented to highlight emerging therapeutic strategies aimed at harnessing the regenerative potential of the fetal epicardium for cardiac repair.
Topics: Animals; Heart Diseases; Humans; Myocardium; Paracrine Communication; Pericardium; Regeneration
PubMed: 31999538
DOI: 10.1161/CIRCRESAHA.119.315857