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

Ian R McCracken, Ross Dobie, Matthew Bennett, Rainha Passi, Abdelaziz Beqqali, Neil C Henderson, Joanne C Mountford, Paul R Riley, Chris P Ponting, Nicola Smart, Mairi Brittan, Andrew H Baker*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 characterise the transcriptome of the human fetal 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 fetal cardiac endothelial cells (EC), 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 arterialisation 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 characterisation 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 fetal 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.

TRANSLATIONAL PERSPECTIVE: Endogenous blood vessel formation in the adult heart following myocardial infarction is insufficient to support adequate survival of the remaining myocardium, often ultimately leading to heart failure. Improved understanding of the mechanisms regulating human coronary vessel formation is required to inform therapeutic strategies to reactivate developmental pathways promoting therapeutic angiogenesis in patients. We applied scRNA-seq to map the transcriptome of the endothelium of the developing human heart. We identified novel transcriptional signatures underlying the cellular heterogeneity and dynamic changes occurring within the developing cardiac endothelium. This included identifying and validating MECOM as a novel regulator of arterial EC identity which may serve as a target for therapeutic neovascularization.

Original languageEnglish
Pages (from-to)2960-2972
Number of pages13
JournalCardiovascular Research
Volume118
Issue number14
Early online date25 Feb 2022
DOIs
Publication statusPublished - 10 Nov 2022

Keywords

  • ANGIOGENESIS
  • ARTERIAL
  • ATLAS
  • CONTRIBUTES
  • CORONARY VASCULATURE
  • Coronary vasculature formation
  • DIFFERENTIATION
  • Endothelial heterogeneity
  • Human cardiac development
  • MAPS
  • MECOM
  • ORGAN
  • PROGENITOR CELLS
  • SPECIFICATION
  • Single-cell RNA sequencing
  • Vascular regeneration
  • HEART

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