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Cited by 539Congenital heart defects researchDevelopmental Biology and Gene RegulationMesenchymal stem cell research

Epicardium-Derived Cells Contribute a Novel Population to the Myocardial Wall and the Atrioventricular Cushions

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Gittenberger-de Groot, Adriana C., Vrancken Peeters, Mark-Paul F.M., Mentink, Monica M.T., Gourdie, Robert G., Poelmann, Robert E.·1998·Circulation Research
DOI 10.1161/01.res.82.10.1043
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Abstract

Abstract —The epicardium and dorsal mesocardium are known to be the source of structures that form the wall of the coronary vessels. Because mouse knockout studies have shown that proper epicardial formation is also essential for myocardial development, we have studied in detail the migration and differentiation of epicardium-derived cells (EPDCs) within the developing heart. We constructed chicken-quail chimeras by grafting the quail epicardial organ, including a piece of primordial liver, at essentially stages 16 and 17. The embryos were studied at stages 25 to 43. To detect quail-derived EPDCs, an anti-quail nucleus antibody was used in combination with several differentiation markers, eg, for muscle actin, for vascular smooth muscle cells, for procollagen-I, for quail endothelium, and for Purkinje fibers. At stages 25 to 31, EPDCs are encountered in the myocardial wall and the subendocardial region. The latter deposition is spatially facilitated as the endocardium protrudes through transient discontinuities in the myocardium to contact the subepicardial layer. Later on, at stages 32 to 43, EPDCs invaded, by way of the atrioventricular sulcus, the atrioventricular cushion tissue. The localization is apparent at the interface with the myocardium, as well as subendocardially, but never within the endocardial lining. The origin of endothelium, smooth muscle cells, and fibroblasts of the coronary vessel wall from the epicardial graft were confirmed in accordance with already published data. The functional role of the novel EPDCs in the subendocardium, myocardium, and atrioventricular cushions remains to be investigated. A close positional relationship is found with the differentiating Purkinje fibers. Furthermore, a regulatory role is postulated in the process of endocardial-mesenchymal transformation. The ultimate fate of EPDCs seems to be a cardiac fibroblast cell line involved in the formation of the fibrous heart skeleton.

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  • AV mesenchymal cells are also generated from the epicardium via EpiMT starting around E12.5.

    “AV mesenchymal cells are also generated from the epicardium via the epicardial-to-mesenchymal transition (EpiMT) starting around E12.5 (Fig. 1a).”

    From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [6]

    The Endocardial Cushion Invasion section reports epicardium-derived cells in the AV cushions of chicken–quail chimeras at stages 32–43, and the Discussion describes epicardial cells transforming into a subepicardial cell population. The paper does not establish that AV mesenchymal cells begin to arise by this route around mouse embryonic day E12.5; its E12.5 reference concerns lethality in mouse knockout models, not the timing of AV cushion invasion. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • AV mesenchyme, the progenitor pool for VICs, is formed early in development through two EMTs from endocardium and epicardium.

    “During mouse embryogenesis, AV mesenchyme, which comprises the progenitor pool for VICs, is formed early in development through two epithelial-to-mesenchymal transitions (EMTs) from distinct cellular sources: endocardium and epicardium4–6”

    From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [6]

    The Discussion describes transformation of epicardial cells into EPDCs and endocardial cells into AV-cushion mesenchyme; the Results report EPDCs in developing valve cushions. But this chicken–quail chimera study does not establish the claim for mouse embryogenesis or identify the AV mesenchyme as the progenitor pool for valve interstitial cells. Its Figure 8 discussion also places epicardial-cell entry into AV cushions later, not at the earliest stage shown. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Via EpiMT, epicardial cells contribute to smooth muscle cells, vasculature, pericytes, and fibroblasts, including those of the AVC and annulus fibrosus.

    “Via EpiMT, epicardial cells contribute to smooth muscle cells, vasculature, pericytes, and fibroblasts, including those of the atrioventricular canal (AVC) and the annulus fibrosus5,6,23,24.”

    From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [6]

    The Abstract reports that epicardial graft cells contribute to coronary-vessel endothelium, smooth muscle cells, and fibroblasts. The Endocardial Cushion Invasion section and Discussion place epicardium-derived cells in the AV cushions and developing fibrous annulus, with evidence of a fibroblastic lineage. Our copy does not identify pericytes as a contribution, so it does not support that part of the claim. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Epithelial-to-mesenchymal transitions (EMTs) of both endocardium and epicardium guide atrioventricular heart valve formation.

    “Epithelial-to-mesenchymal transitions (EMTs) of both endocardium and epicardium guide atrioventricular heart valve formation”

    From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [6]

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Cites

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Authors
Gittenberger-de Groot, A. C., Vrancken Peeters, M.-P. F. M., Mentink, M. M. T., Gourdie, R. G., & Poelmann, R. E.
Affiliations
  • From the Department of Anatomy and Embryology (A.C.G.-de G., M.-P.F.M.V.P., M.M.T.M., R.E.P.), Leiden University Medical Center, Leiden, Netherlands, and the Department of Cell Biology and Anatomy (R.G.G.), Cardiovascular Developmental Biology Center, Medical University of South Carolina, Charleston, SC.
  • Medical University of South Carolina (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1998-06
Volume
82
Issue
10
Pages
1043-1052
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/01.res.82.10.1043
OpenAlex
W2075396495
Cited by
539
References
1
Citations by year
2026: 6 · 2025: 11 · 2024: 25 · 2023: 16 · 2022: 9 · 2021: 20 · 2020: 18 · 2019: 20 · 2018: 24 · 2017: 15 · 2016: 34 · 2015: 29 · 2014: 14 · 2013: 26 · 2012: 40
FWCI
3.60
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
March of Dimes Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
epicardium, myocardial development, atrioventricular cushion, subendocardium, Purkinje fibers, cardiac fibroblasts, cell migration and differentiation
MeSH terms
Animals, Atrioventricular Node, Chick Embryo, Coturnix, Heart, Morphogenesis, Myocardium, Pericardium, Purkinje Fibers, Mice

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