Sox7-Positive Endothelial Progenitors Establish Coronary Arteries and Govern Ventricular Compaction

Authors

Ivy Kn Chiang
David Humphrey
Richard J Mills
Peter Kaltzis
Shikha Pachauri
Matthew Graus
Diptarka Saha
Zhijian Wu
Paul Young
Choon Boon Sim
Tara Davidson
Andres Hernandez-Garcia
Chad A Shaw
Alexander Renwick
Daryl A Scott
Enzo R Porrello
Emily S Wong
James E Hudson
Kristy Red-Horse
Gonzalo Del Monte-Nieto
Mathias Francois

Publication Date

10-9-2023

Journal

EMBO Reports

DOI

10.15252/embr.202255043

PMID

37551717

PMCID

PMC10561369

PubMedCentral® Posted Date

8-8-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Coronary Vessels, Endothelial Cells, Myocytes, Cardiac, Gene Expression Regulation, Endothelium, SOXF Transcription Factors, arterial cell fate, coronary vessels, heart development, non‐compaction cardiomyopathy, SOX transcription factor, Cardiovascular System, Development, Vascular Biology & Angiogenesis

Abstract

The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial-specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non-compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, which govern coronary arterial specification. Upon Sox7 endothelial-specific deletion, single-nuclei transcriptomics analysis identifies the depletion of a subset of Sox9/Gpc3-positive endocardial progenitor cells and an increase in erythro-myeloid cell lineages. Fate mapping analysis reveals that a subset of Sox7-null endothelial cells transdifferentiate into hematopoietic but not cardiomyocyte lineages. Our findings determine that Sox7 maintains cardiac endothelial cell identity, which is crucial to the cellular cross-talk that drives ventricular compaction and coronary artery development.