Origin, Fate, and Function of Epicardium-Derived Cells (EPDCs) in Normal and Abnormal Cardiac Development

During heart development, cells of the primary and secondary heart field give rise to the myocardial component of the heart. The neural crest and epicardium provide the heart with a considerable amount of nonmyocardial cells that are indispensable for correct heart development. During the past 2 decades, the importance of epicardium-derived cells (EPDCs) in heart formation became increasingly clear. The epicardium is embryologically formed by the outgrowth of proepicardial cells over the naked heart tube. Following epithelial-mesenchymal transformation, EPDCs form the subepicardial mesenchyme and subsequently migrate into the myocardium, and differentiate into smooth muscle cells and fibroblasts. They contribute to the media of the coronary arteries, to the atrioventricular valves, and the fibrous heart skeleton. Furthermore, they are important for the myocardial architecture of the ventricular walls and for the induction of Purkinje fiber formation.Whereas the exact signaling cascades in EPDC migration and function still need to be elucidated, recent research has revealed several factors that are involved in EPDC migration and specialization, and in the cross-talk between EPDCs and other cells during heart development. Among these factors are the Ets transcription factors Ets-1 and Ets-2. New data obtained with lentiviral antisense constructs targeting Ets-1 and Ets-2 specifically in the epicardium indicate that both factors are independently involved in the migratory behavior of EPDCs. Ets-2 seems to be especially important for the migration of EPDCs into the myocardial wall, and to subendocardial positions in the atrioventricular cushions and the trabeculae.With respect to the clinical importance of correct EPDC development, the relation with coronary arteriogenesis has been noted well before. In this review, we also propose a role for EPDCs in cardiac looping, and emphasize their contribution to the development of the valves and myocardial architecture. Lastly, we focus on the congenital heart anomalies that might be caused primarily by an epicardial developmental defect.

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Abnormal Cardiac Development in the Absence of Heart Glycogen

Molecular and Cellular Biology ◽

10.1128/mcb.24.16.7179-7187.2004 ◽

2004 ◽

Vol 24 (16) ◽

pp. 7179-7187 ◽

Cited By ~ 68

Author(s):

Bartholomew A. Pederson ◽

Hanying Chen ◽

Jill M. Schroeder ◽

Weinian Shou ◽

Anna A. DePaoli-Roach ◽

...

Keyword(s):

Cardiac Function ◽

Cardiac Muscle ◽

Heart Development ◽

Congenital Heart ◽

Cardiac Development ◽

Glycogen Synthase ◽

Heart Defects ◽

Mendelian Inheritance ◽

And Function ◽

Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

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The Expanding Role for Retinoid Signaling in Heart Development

The Scientific World JOURNAL ◽

10.1100/tsw.2008.39 ◽

2008 ◽

Vol 8 ◽

pp. 194-211 ◽

Cited By ~ 20

Author(s):

Loretta L. Hoover ◽

Elizabeth G. Burton ◽

Bonnie A. Brooks ◽

Steven W. Kubalak

Keyword(s):

Vitamin A ◽

Heart Development ◽

Cardiac Development ◽

Tube Formation ◽

Conditional Knockout ◽

Heart Tube ◽

Developmental Defects ◽

Retinoid Signaling ◽

Developing Heart ◽

Cardiac Lineage

The importance of retinoid signaling during cardiac development has long been appreciated, but recently has become a rapidly expanding field of research. Experiments performed over 50 years ago showed that too much or too little maternal intake of vitamin A proved detrimental for embryos, resulting in a cadre of predictable cardiac developmental defects. Germline and conditional knockout mice have revealed which molecular players in the vitamin A signaling cascade are potentially responsible for regulating specific developmental events, and many of these molecules have been temporally and spatially characterized. It is evident that intact and controlled retinoid signaling is necessary for each stage of cardiac development to proceed normally, including cardiac lineage determination, heart tube formation, looping, epicardium formation, ventricular maturation, chamber and outflow tract septation, and coronary arteriogenesis. This review summarizes many of the significant milestones in this field and particular attention is given to recently uncovered cross-talk between retinoid signaling and other developmentally significant pathways. It is our hope that this review of the role of retinoid signaling during formation, remodeling, and maturation of the developing heart will serve as a tool for future discoveries.

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Dissecting the Complexity of Early Heart Progenitor Cells

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd9010005 ◽

2021 ◽

Vol 9 (1) ◽

pp. 5

Author(s):

Miquel Sendra ◽

Jorge Domínguez ◽

Miguel Torres ◽

Oscar Ocaña

Keyword(s):

Progenitor Cells ◽

Heart Development ◽

Functional Role ◽

Cardiac Development ◽

Heart Defects ◽

Heart Tube ◽

Cell Sources ◽

Key Aspects ◽

Functional Analyses ◽

Lineage Diversification

Early heart development depends on the coordinated participation of heterogeneous cellsources. As pioneer work from Adriana C. Gittenberger-de Groot demonstrated, characterizing thesedistinct cell sources helps us to understand congenital heart defects. Despite decades of researchon the segregation of lineages that form the primitive heart tube, we are far from understanding itsfull complexity. Currently, single-cell approaches are providing an unprecedented level of detail oncellular heterogeneity, offering new opportunities to decipher its functional role. In this review, wewill focus on three key aspects of early heart morphogenesis: First, the segregation of myocardial andendocardial lineages, which yields an early lineage diversification in cardiac development; second,the signaling cues driving differentiation in these progenitor cells; and third, the transcriptionalheterogeneity of cardiomyocyte progenitors of the primitive heart tube. Finally, we discuss howsingle-cell transcriptomics and epigenomics, together with live imaging and functional analyses, willlikely transform the way we delve into the complexity of cardiac development and its links withcongenital defects.

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The quintessence of the making of the heart

Cardiology in the Young ◽

10.1017/s1047951103000337 ◽

2003 ◽

Vol 13 (2) ◽

pp. 175-183 ◽

Cited By ~ 11

Author(s):

Adriana C. Gittenberger-de Groot

Keyword(s):

Neural Crest ◽

Heart Development ◽

Basic Science ◽

Body Wall ◽

Cardiac Development ◽

Vascular System ◽

Conduction System ◽

Cardiac Insufficiency ◽

Heart Tube

In my Mannheimer lecture, designed to meet the needs of a mainly clinical audience, I present aspects of cardiac development that link basic science to clinically relevant problems. During development of the cardiac tube, and its subsequent changes as a dextrally looped structure, which is still connected to the dorsal body wall by a venous and an arterial pole, there are basic requirements. These consist of the development of myocardium, endocardium and the interposed cardiac jelly from the cardiogenic plates. In this primitive heart tube, septation and valvar formation then take place to convert it into a four-chambered heart. I demonstrate that the refining of the above events cannot take place without the addition of extracardiac populations of cells. These are presented as the “quintessence of heart development”, and consist of cells derived from the neural crest, along with epicardially derived cells. Without these contributions, the embryos uniformly die of cardiac insufficiency. Important contributions are made by the cells derived from the neural crest to septation and the formation of the arterial valves, and possibly in differentiation of the central conduction system. The epicardially derived cells are essential for formation of the interstitial fibroblasts and the myocardium, as well as the coronary vascular system. I conclude by discussing specific malformations of the heart that might be linked to these extracardiac contributions.

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miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations

International Journal of Molecular Sciences ◽

10.3390/ijms21031158 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1158 ◽

Cited By ~ 2

Author(s):

Sarah C. Hoelscher ◽

Theresia Stich ◽

Anne Diehm ◽

Harald Lahm ◽

Martina Dreßen ◽

...

Keyword(s):

Pluripotent Stem Cells ◽

Heart Development ◽

Regulatory Networks ◽

Progenitor Cell ◽

Cardiac Development ◽

Loss Of Function ◽

And Function ◽

Cardiac Transcription Factors ◽

Beating Frequency

MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased Isl1, Sfrp5, and Hcn4 (cardiac transcription factors) but reduced Irx4 at the onset of cardiogenesis, (2) upregulated Isl1-positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte marker Myl2 accompanied by a reduced beating frequency of early cardiomyocytes. Overexpression of miR-128a (4) diminished the expression of Isl1, Sfrp5, Nkx2.5, and Mef2c, but increased Irx4, (5) enhanced NkxCE-positive CPCs, and (6) favored nodal-like cardiomyocytes (Tnnt2+, Myh6+, Shox2+) accompanied by increased beating frequencies. In summary, we demonstrated that miR-128a plays a so-far unknown role in early heart development by affecting the timing of CPC differentiation into various cardiomyocyte subtypes.

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Myocardial Notch-Rbpj deletion does not affect heart development or function

10.1101/393348 ◽

2018 ◽

Author(s):

Alejandro Salguero-Jiménez ◽

Joaquim Grego-Bessa ◽

Gaetano D’Amato ◽

Luis J. Jiménez-Borreguero ◽

José Luis de la Pompa

Keyword(s):

Notch Signaling ◽

Heart Development ◽

Cardiac Development ◽

Heart Function ◽

Physiological Role ◽

Double Outlet Right Ventricle ◽

Cardiac Valves ◽

Myocardial Development ◽

Normal Expression ◽

And Function

AbstractDuring vertebrate cardiac development NOTCH signaling activity in the endocardium is essential for the crosstalk between endocardium and myocardium that initiates ventricular trabeculation and valve primordium formation. This crosstalk leads later to the maturation and compaction of the ventricular chambers and the morphogenesis of the cardiac valves, and its alteration may lead to disease. Although endocardial NOTCH signaling has been shown to be crucial for heart development, its physiological role in the myocardium has not been clearly established. Here we have used a genetic strategy to evaluate the role of NOTCH in myocardial development. We have inactivated the unique and ubiquitous NOTCH effector RBPJ in the early cardiomyocytes progenitors, and examined its consequences in cardiac development and function. Our results demonstrate that mice with cTnT-Cre-mediated myocardial-specific deletion of Rbpj develop to term, with homozygous mutant animals showing normal expression of cardiac development markers, and normal adult heart function. Similar observations have been obtained after Notch1 deletion with cTnT-Cre. We have also deleted Rbpj in both myocardial and endocardial progenitor cells, using the Nkx2.5-Cre driver, resulting in ventricular septal defect (VSD), double outlet right ventricle (DORV), and bicuspid aortic valve (BAV), due to NOTCH signaling abrogation in the endocardium of cardiac valves territories. Our data demonstrate that NOTCH-RBPJ inactivation in the myocardium does not affect heart development or adult cardiac function.

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The ECM as a driver of heart development and repair

Development ◽

10.1242/dev.191320 ◽

2021 ◽

Vol 148 (5) ◽

pp. dev191320

Author(s):

Christopher J. Derrick ◽

Emily S. Noël

Keyword(s):

Extracellular Matrix ◽

Heart Development ◽

Cardiac Development ◽

Cardiac Cells ◽

Heart Regeneration ◽

Heart Morphogenesis ◽

Developing Heart ◽

Spatiotemporal Changes ◽

And Function

ABSTRACTThe developing heart is formed of two tissue layers separated by an extracellular matrix (ECM) that provides chemical and physical signals to cardiac cells. While deposition of specific ECM components creates matrix diversity, the cardiac ECM is also dynamic, with modification and degradation playing important roles in ECM maturation and function. In this Review, we discuss the spatiotemporal changes in ECM composition during cardiac development that support distinct aspects of heart morphogenesis. We highlight conserved requirements for specific ECM components in human cardiac development, and discuss emerging evidence of a central role for the ECM in promoting heart regeneration.

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A Pictorial Account of Heart Development: Spatial and Temporal Aspects of The Human Embryonic Heart Between 3.5 and 8 Weeks of Development

10.21203/rs.3.rs-129074/v1 ◽

2020 ◽

Author(s):

Jill Hikspoors ◽

Nuthmethee Kruepunga ◽

Greet Mommen ◽

Eleonore Koehler ◽

Robert Anderson ◽

...

Keyword(s):

3D Reconstruction ◽

Heart Development ◽

Cardiac Development ◽

Heart Tube ◽

Segmental Analysis ◽

3 Dimensional ◽

Temporal Aspects ◽

Age Dependent ◽

Interactive 3D ◽

Sequential Segmental Analysis

Abstract Heart development is topographically complex and requires visualization to understand its progression. No comprehensive 3-dimensional primer of human cardiac development is currently available. We prepared detailed reconstructions of 12 hearts between 3.5 and 8 weeks post fertilization, using Amira® 3D-reconstruction and Cinema4D®-remodeling software. The models were visualized as calibrated interactive 3D-PDFs. We describe the developmental appearance and subsequent remodeling of 70 different structures incrementally, using sequential segmental analysis. Pictorial timelines of structures highlight age-dependent events, while graphs visualize growth and spiraling of the wall of the heart tube. The basic cardiac layout is established between 3.5 and 4.5 weeks. Septation at the venous pole is completed at 6 weeks. Between 5.5 and 6.5 weeks, as the outflow tract becomes incorporated in the ventricles, the spiraling course of its subaortic and subpulmonary channels is transferred to the intrapericardial arterial trunks. The remodeling of the interventricular foramen is complete at 7 weeks.

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PDGFRα: Expression and Function during Mitral Valve Morphogenesis

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8030028 ◽

2021 ◽

Vol 8 (3) ◽

pp. 28

Author(s):

Kelsey Moore ◽

Diana Fulmer ◽

Lilong Guo ◽

Natalie Koren ◽

Janiece Glover ◽

...

Keyword(s):

Mitral Valve ◽

Primary Cilia ◽

Growth Factor Receptor ◽

Akt Phosphorylation ◽

Valve Development ◽

Biochemical Assays ◽

Factor Receptor Alpha ◽

Mesenchymal Transformation ◽

And Function

Mitral valve prolapse (MVP) is a common form of valve disease and can lead to serious secondary complications. The recent identification of MVP causal mutations in primary cilia-related genes has prompted the investigation of cilia-mediated mechanisms of disease inception. Here, we investigate the role of platelet-derived growth factor receptor-alpha (PDGFRα), a receptor known to be present on the primary cilium, during valve development using genetically modified mice, biochemical assays, and high-resolution microscopy. While PDGFRα is expressed throughout the ciliated valve interstitium early in development, its expression becomes restricted on the valve endocardium by birth and through adulthood. Conditional ablation of Pdgfra with Nfatc1-enhancer Cre led to significantly enlarged and hypercellular anterior leaflets with disrupted endothelial adhesions, activated ERK1/2, and a dysregulated extracellular matrix. In vitro culture experiments confirmed a role in suppressing ERK1/2 activation while promoting AKT phosphorylation. These data suggest that PDGFRα functions to suppress mesenchymal transformation and disease phenotypes by stabilizing the valve endocardium through an AKT/ERK pathway.

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Outflow Tract Formation—Embryonic Origins of Conotruncal Congenital Heart Disease

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8040042 ◽

2021 ◽

Vol 8 (4) ◽

pp. 42

Author(s):

Sonia Stefanovic ◽

Heather C. Etchevers ◽

Stéphane Zaffran

Keyword(s):

Congenital Heart ◽

Cardiac Development ◽

Heart Defects ◽

Dynamic Structure ◽

Cell Types ◽

Outflow Tract ◽

Heart Tube ◽

Heart Field ◽

Multiple Cell ◽

The Many

Anomalies in the cardiac outflow tract (OFT) are among the most frequent congenital heart defects (CHDs). During embryogenesis, the cardiac OFT is a dynamic structure at the arterial pole of the heart. Heart tube elongation occurs by addition of cells from pharyngeal, splanchnic mesoderm to both ends. These progenitor cells, termed the second heart field (SHF), were first identified twenty years ago as essential to the growth of the forming heart tube and major contributors to the OFT. Perturbation of SHF development results in common forms of CHDs, including anomalies of the great arteries. OFT development also depends on paracrine interactions between multiple cell types, including myocardial, endocardial and neural crest lineages. In this publication, dedicated to Professor Andriana Gittenberger-De Groot and her contributions to the field of cardiac development and CHDs, we review some of her pioneering studies of OFT development with particular interest in the diverse origins of the many cell types that contribute to the OFT. We also discuss the clinical implications of selected key findings for our understanding of the etiology of CHDs and particularly OFT malformations.

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