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Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction

ABSTRACT: Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. Here, we used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behaviour. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, down-regulated by Ino80-deficiency, which functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) AQ6 up-regulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation. These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE175589 | GEO | 2021/12/30

REPOSITORIES: GEO

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Gene expression analysis from bulk RNA isolated from embryonic mouse hearts at time points E13.5 and E14.5 with and without disruption of endothelial Ino80

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