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Cited by 263Congenital heart defects researchDevelopmental Biology and Gene RegulationCardiac Fibrosis and Remodeling

Epicardially derived fibroblasts preferentially contribute to the parietal leaflets of the atrioventricular valves in the murine heart

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Wessels, Andy, van den Hoff, Maurice J.B., Adamo, Richard F., Phelps, Aimee L., Lockhart, Marie M., Sauls, Kimberly, Briggs, Laura E., Norris, Russell A. +4 more·2012·Developmental Biology
DOI 10.1016/j.ydbio.2012.04.020PMC PMC3358438
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Abstract

The importance of the epicardium for myocardial and valvuloseptal development has been well established; perturbation of epicardial development results in cardiac abnormalities, including thinning of the ventricular myocardial wall and malformations of the atrioventricular valvuloseptal complex. To determine the spatiotemporal contribution of epicardially derived cells to the developing fibroblast population in the heart, we have used a mWt1/IRES/GFP-Cre mouse to trace the fate of EPDCs from embryonic day (ED)10 until birth. EPDCs begin to populate the compact ventricular myocardium around ED12. The migration of epicardially derived fibroblasts toward the interface between compact and trabecular myocardium is completed around ED14. Remarkably, epicardially derived fibroblasts do not migrate into the trabecular myocardium until after ED17. Migration of EPDCs into the atrioventricular cushion mesenchyme commences around ED12. As development progresses, the number of EPDCs increases significantly, specifically in the leaflets which derive from the lateral atrioventricular cushions. In these developing leaflets the epicardially derived fibroblasts eventually largely replace the endocardially derived cells. Importantly, the contribution of EPDCs to the leaflets derived from the major AV cushions is very limited. The differential contribution of EPDCs to the various leaflets of the atrioventricular valves provides a new paradigm in valve development and could lead to new insights into the pathogenesis of abnormalities that preferentially affect individual components of this region of the heart. The notion that there is a significant difference in the contribution of epicardially and endocardially derived cells to the individual leaflets of the atrioventricular valves has also important pragmatic consequences for the use of endocardial and epicardial cre-mouse models in studies of heart development.

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  • 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 [5]

    The Introduction says early AV-cushion mesenchyme derives from endocardial EMT and later gives rise to valve interstitial cells. The Results say nearly all cushion mesenchymal cells are endocardially derived at ED12, with very limited epicardial contribution; epicardially derived cells populate the lateral cushions later, around ED14–14.5. This contradicts the claim that early AV mesenchyme forms through EMTs from both sources. (LLM, conf=0.87)

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  • 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 [5]

    The Introduction reports that epicardial cells undergo a mesenchymal transition and give rise to cardiac fibroblasts and coronary smooth muscle cells. The Results and Discussion describe their contribution to AV cushions and valve fibroblasts, and to tissue involved in AV insulation. The copy does not establish the claimed contribution to pericytes; its Results describe a contribution to coronary endothelium as contentious, so the broader claim about vasculature is not fully supported. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • At E12.5, EpiMT is initiated in epicardial cells lining the outside of the AVC.

    “At E12.5, EpiMT is initiated in epicardial cells lining the outside of the AVC5,59.”

    From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [5]

    The Abstract says EPDCs begin migrating into atrioventricular cushion mesenchyme around ED12, and the Discussion (‘The epicardium and AV insulation’; page unavailable) describes cells leaving the epicardial epithelium near the AV sulcus and gradually acquiring a mesenchymal phenotype. These passages support the location and process, but do not establish that EpiMT itself is initiated at E12.5. (LLM, conf=0.82)

    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 [5]

  • 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 [5]

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Authors
Wessels, A., van den Hoff, M. J. B., Adamo, R. F., Phelps, A. L., Lockhart, M. M., Sauls, K., Briggs, L. E., Norris, R. A., van Wijk, B., Perez-Pomares, J. M., Dettman, R. W., & Burch, J. B. E.
Affiliations
  • Medical University of South Carolina (US)
  • Children's Hospital of Philadelphia (US)
  • Northwestern University (US)
  • Fox Chase Cancer Center (US)
Corresponding author
Wessels, Andy
ORCID
Venue
Developmental Biology
Publisher
Elsevier BV
Published
2012-06
Volume
366
Issue
2
Pages
111-124
ISSN
0012-1606 (ISSN-L)
DOI
10.1016/j.ydbio.2012.04.020
PMC
PMC3358438
OpenAlex
W2059082931
Cited by
263
References
1
Citations by year
2026: 18 · 2025: 8 · 2024: 21 · 2023: 11 · 2022: 16 · 2021: 23 · 2020: 23 · 2019: 20 · 2018: 29 · 2017: 10 · 2016: 22 · 2015: 22 · 2014: 17 · 2013: 11 · 2012: 12
FWCI
7.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
  • American Heart Association (11PRE7310036, C06 RR015455, HL007260)
  • National Institutes of Health (1c06rr015455-01a1, 1c06rr018823-01)
  • National Heart, Lung, and Blood Institute (HL055373, HL007260, T32HL007260, HL084285, R01HL033756, R01HL084285, R01HL055373)
  • National Institute of General Medical Sciences (T32GM008716, 5T32-GM008716-12)
  • National Center for Research Resources (RR 015455, P20RR016434, C06 RR-015455, C06 RR-018823)
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 › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
epicardium, atrioventricular valves, valve leaflets, atrioventricular cushion, heart development, lineage tracing, fibroblast migration, trabecular myocardium
MeSH terms
Animals, Fibroblasts, Heart, Heart Valves, Heart Ventricles, Pericardium, Organogenesis, Embryonic Development, Mice

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