Multi-species Meta-Analysis Identifies Transcriptional Signatures Associated with Cardiac Endothelial Responses in the Ischaemic Heart.

Ziwen Li,Emmanouil G. Solomonidis,Bronwyn Berkeley,Michelle Nga Huen Tang,Katherine Ross Stewart,Daniel Perez-Vicencio,Ian R. McCracken,Ana Mishel Spiroski,Gillian A. Gray,Anna K. Barton,Stephanie L. Sellers,Paul R. Riley,Andrew H. Baker,Mairi Brittan

Cardiovascular research（2023）SCI 1区SCI 2区

Univ Edinburgh | Univ British Columbia | Univ Oxford

Cited 7|Views4

Abstract

AbstractAimMyocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration.Methods and resultsWe carried out a comprehensive meta-analysis of integrated single-cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularization. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1, and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularization.ConclusionWe present a high-resolution single-cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development.

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Key words

scRNA-seq meta-analysis,ischaemic heart disease,vascular regeneration

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