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Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression

AIMS: Coronary vasculature formation is a critical event during cardiac development, essential for heart function throughout perinatal and adult life. However, current understanding of coronary vascular development has largely been derived from transgenic mouse models. The aim of this study was to c...

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Autores principales: McCracken, Ian R, Dobie, Ross, Bennett, Matthew, Passi, Rainha, Beqqali, Abdelaziz, Henderson, Neil C, Mountford, Joanne C, Riley, Paul R, Ponting, Chris P, Smart, Nicola, Brittan, Mairi, Baker, Andrew H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648824/
https://www.ncbi.nlm.nih.gov/pubmed/35212715
http://dx.doi.org/10.1093/cvr/cvac023
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author McCracken, Ian R
Dobie, Ross
Bennett, Matthew
Passi, Rainha
Beqqali, Abdelaziz
Henderson, Neil C
Mountford, Joanne C
Riley, Paul R
Ponting, Chris P
Smart, Nicola
Brittan, Mairi
Baker, Andrew H
author_facet McCracken, Ian R
Dobie, Ross
Bennett, Matthew
Passi, Rainha
Beqqali, Abdelaziz
Henderson, Neil C
Mountford, Joanne C
Riley, Paul R
Ponting, Chris P
Smart, Nicola
Brittan, Mairi
Baker, Andrew H
author_sort McCracken, Ian R
collection PubMed
description AIMS: Coronary vasculature formation is a critical event during cardiac development, essential for heart function throughout perinatal and adult life. However, current understanding of coronary vascular development has largely been derived from transgenic mouse models. The aim of this study was to characterize the transcriptome of the human foetal cardiac endothelium using single-cell RNA sequencing (scRNA-seq) to provide critical new insights into the cellular heterogeneity and transcriptional dynamics that underpin endothelial specification within the vasculature of the developing heart. METHODS AND RESULTS: We acquired scRNA-seq data of over 10 000 foetal cardiac endothelial cells (ECs), revealing divergent EC subtypes including endocardial, capillary, venous, arterial, and lymphatic populations. Gene regulatory network analyses predicted roles for SMAD1 and MECOM in determining the identity of capillary and arterial populations, respectively. Trajectory inference analysis suggested an endocardial contribution to the coronary vasculature and subsequent arterialization of capillary endothelium accompanied by increasing MECOM expression. Comparative analysis of equivalent data from murine cardiac development demonstrated that transcriptional signatures defining endothelial subpopulations are largely conserved between human and mouse. Comprehensive characterization of the transcriptional response to MECOM knockdown in human embryonic stem cell-derived EC (hESC-EC) demonstrated an increase in the expression of non-arterial markers, including those enriched in venous EC. CONCLUSIONS: scRNA-seq of the human foetal cardiac endothelium identified distinct EC populations. A predicted endocardial contribution to the developing coronary vasculature was identified, as well as subsequent arterial specification of capillary EC. Loss of MECOM in hESC-EC increased expression of non-arterial markers, suggesting a role in maintaining arterial EC identity.
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spelling pubmed-96488242022-11-14 Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression McCracken, Ian R Dobie, Ross Bennett, Matthew Passi, Rainha Beqqali, Abdelaziz Henderson, Neil C Mountford, Joanne C Riley, Paul R Ponting, Chris P Smart, Nicola Brittan, Mairi Baker, Andrew H Cardiovasc Res Original Article AIMS: Coronary vasculature formation is a critical event during cardiac development, essential for heart function throughout perinatal and adult life. However, current understanding of coronary vascular development has largely been derived from transgenic mouse models. The aim of this study was to characterize the transcriptome of the human foetal cardiac endothelium using single-cell RNA sequencing (scRNA-seq) to provide critical new insights into the cellular heterogeneity and transcriptional dynamics that underpin endothelial specification within the vasculature of the developing heart. METHODS AND RESULTS: We acquired scRNA-seq data of over 10 000 foetal cardiac endothelial cells (ECs), revealing divergent EC subtypes including endocardial, capillary, venous, arterial, and lymphatic populations. Gene regulatory network analyses predicted roles for SMAD1 and MECOM in determining the identity of capillary and arterial populations, respectively. Trajectory inference analysis suggested an endocardial contribution to the coronary vasculature and subsequent arterialization of capillary endothelium accompanied by increasing MECOM expression. Comparative analysis of equivalent data from murine cardiac development demonstrated that transcriptional signatures defining endothelial subpopulations are largely conserved between human and mouse. Comprehensive characterization of the transcriptional response to MECOM knockdown in human embryonic stem cell-derived EC (hESC-EC) demonstrated an increase in the expression of non-arterial markers, including those enriched in venous EC. CONCLUSIONS: scRNA-seq of the human foetal cardiac endothelium identified distinct EC populations. A predicted endocardial contribution to the developing coronary vasculature was identified, as well as subsequent arterial specification of capillary EC. Loss of MECOM in hESC-EC increased expression of non-arterial markers, suggesting a role in maintaining arterial EC identity. Oxford University Press 2022-02-25 /pmc/articles/PMC9648824/ /pubmed/35212715 http://dx.doi.org/10.1093/cvr/cvac023 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
McCracken, Ian R
Dobie, Ross
Bennett, Matthew
Passi, Rainha
Beqqali, Abdelaziz
Henderson, Neil C
Mountford, Joanne C
Riley, Paul R
Ponting, Chris P
Smart, Nicola
Brittan, Mairi
Baker, Andrew H
Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression
title Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression
title_full Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression
title_fullStr Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression
title_full_unstemmed Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression
title_short Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression
title_sort mapping the developing human cardiac endothelium at single-cell resolution identifies mecom as a regulator of arteriovenous gene expression
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648824/
https://www.ncbi.nlm.nih.gov/pubmed/35212715
http://dx.doi.org/10.1093/cvr/cvac023
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