Coordination of endothelial cell positioning and fate specification by the epicardium
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The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.
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The processes underlying AV EpiMT remain poorly characterized, as few studies assessing EpiMT focus on chamber epicardium.
“However, the processes underlying AV EpiMT remain poorly characterized, as the few studies assessing EpiMT focus on chamber epicardium25–29.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [27]
A distinct population of Hic1-expressing EPDCs is identified from chamber epicardium data from Quijada et al.
“we also identify a distinct population of Hic1-expressing EPDCs from chamber epicardium data from Quijada et al.27.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [27]
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Recent Progress in Cardiovascular Research Involving Single-Cell Omics Approaches
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Self-citation
- Authors
- Quijada, P., Trembley, M. A., Misra, A., Myers, J. A., Baker, C. D., Pérez-Hernández, M., Myers, J. R., Dirkx, R. A., Cohen, E. D., Delmar, M., Ashton, J. M., & Small, E. M.
- Affiliations
- University of California, Los Angeles (US)
- University of Rochester Medicine (US)
- New York University (US)
- Corresponding author
- Small, Eric M.
- ORCID
- Venue
- Nature Communications
- Published
- 2021-07-06
- Volume
- 12
- Issue
- 1
- Pages
- 4155-4155
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8260743
- OpenAlex
- W3181267383
- Cited by
- 50
- References
- 72
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 13 · 2023: 10 · 2022: 4 · 2021: 3 · 2013: 1
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (T32HL066988, F32HL134206, R01HL136179, R01HL134328, R01HL145911, R01HL146514)
- American Heart Association (19CDA34590003, 20PRE35210597)
- Excellence Scholarship for the Rafael del Pino Foundation
- Fondation Leducq Transatlantic Network
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- epicardium, coronary vasculature development, Slit2, epithelial-mesenchymal transition, chemokines, MRTF, paracrine signaling, mesothelium, heart development
- MeSH terms
- Slit Homolog 2 Protein, Myocardin, Animals, Coronary Vessels, Embryo, Mammalian, Heart, Mice, Inbred C57BL, Nerve Tissue Proteins, Nuclear Proteins, Pericardium, Transcription Factors, Signal Transduction, Trans-Activators, Gene Expression, Chemokines, Serum Response Factor, Intercellular Signaling Peptides and Proteins, Endothelial Cells, Mice, Epithelial-Mesenchymal Transition, Transcriptome
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