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 remodeler gene Ino80 results in defective coronary vessel development that leads to ventricular noncompaction 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 behavior. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) upregulated 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.

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction

“…Furthermore, CD31 immunofluorescence also showed the decreased thickness of the compact zone and increased thickness of the trabecular layer in eKO mice (Figure 3H; Figure S2D). In addition, as it is reported that ventricular noncompaction is associated with increased cardiomyocyte maturation, 30 quantitative polymerase chain reaction (qPCR) was performed on samples from E15.5 control and eKO embryonic mouse ventricles to determine the expression levels of cardiomyocyte maturation markers. Tnnt2 (troponin T2), Tnni1 (troponin i1), Tnni3 (troponin i3) and Myh6 (myosin heavy chain 6) were upregulated in ETS1 eKO mice compared with littermate controls (Figure S2E).…”

Placental inflammation leads to abnormal embryonic heart development

“…3-D imaging using high resolution episcopic microscopy revealed increased trabeculation of the ventricular walls of hearts from NDPI embryos, compared to controls (Figure 3C). Recent studies have demonstrated that dysregulation of coronary endothelial cells promotes the development of LVNC 23, 25, 26 . With this in mind, we interrogated the status of the endothelial cells (ECs) within the embryonic heart.…”

Angiocrine IGFBP3 Spatially Coordinates IGF Signaling During Neonatal Cardiac Regeneration

“…40 IGF-as well as non-IGF-related functions of IGFBP3 have been well-characterized, which are pleiotropic, context-specific, and range from antiproliferative to pro-apoptotic to pro-proliferative. 41–44 Since the rich body of work on Igfbp3 did not obviate its consideration as a pro-regenerative secreted factor, and because its expression pattern in the heart after injury showed a distinct regeneration-associated signature, we proceeded to fully interrogate the role of Igfbp3 during neonatal regeneration.…”