CCBE1 in Cardiac Development and Disease

Abstract

The collagen- and calcium-binding EGF-like domains 1 (CCBE1) is a secreted protein extensively described as indispensable for lymphangiogenesis during development enhancing VEGF-C signaling. In human patients, mutations in CCBE1 have been found to cause Hennekam syndrome, an inherited disease characterized by malformation of the lymphatic system that presents a wide variety of symptoms such as primary lymphedema, lymphangiectasia, and heart defects. Importantly, over the last decade, an essential role for CCBE1 during heart development is being uncovered. In mice, Ccbe1 expression was initially detected in distinct cardiac progenitors such as first and second heart field, and the proepicardium. More recently, Ccbe1 expression was identified in the epicardium and sinus venosus (SV) myocardium at E11.5–E13.5, the stage when SV endocardium–derived (VEGF-C dependent) coronary vessels start to form. Concordantly, CCBE1 is required for the correct formation of the coronary vessels and the coronary artery stem in the mouse. Additionally, Ccbe1 was found to be enriched in mouse embryonic stem cells (ESC) and revealed as a new essential gene for the differentiation of ESC-derived early cardiac precursor cell lineages. Here, we bring an up-to-date review on the role of CCBE1 in cardiac development, function, and human disease implications. Finally, we envisage the potential of this molecule’s functions from a regenerative medicine perspective, particularly novel therapeutic strategies for heart disease.

A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity

“…4c). In the EPDCs, we found SEMA3D, involved in concerted endothelial cell migration 36 ; CCBE1, important in mouse cardiac development 37 ; EGFL6, associated with angiogenesis 38 , and GPC3, reported to modulate WNT signaling 39 . Overall, these results suggested further that these epicardial cells are EPDCs no longer on the surface of the heart.…”

Roles for RERE in lymphatic endothelial cell proliferation and survival, and human cystic lymphatic malformations

“…The unique lymphatic presentation of this case of NEBDEH, with only mild neurological findings and absence of cardiac abnormalities, could be due to the truncating LOF variant observed in RERE , as individuals with point mutations in the commonly affected Atrophin-like domain of RERE have more severe NEBDEH phenotypes than their counterparts with LOF variants (7). There is significant overlap between neuronal, cardiac and lymphatic developmental genes, and RA is a well-established modulator of neuronal differentiation in addition to regulating the earliest stages of lymphangiogenesis (1, 19, 33, 35). Lymphatic endothelial cell dysfunction has also been described in patients with neonatal congenital heart defects and chylothorax (36).…”

Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema

“…VEGF-C biological effect is enhanced by the collagen- and calcium-binding EGF domains 1 (CCBE1) along with a disintegrin and metalloproteinase with thrombospondin motifs-3 (ADAMTS3) protease (Jha et al, 2017 ). CCBE1 is a secreted molecule involved in lymphatic vasculature development and mutations in CCBE1 were identified in patients with Hennekam syndrome, a rare autosomal recessive disorder of lymphatic development leading to primary LD (Bonet et al, 2022 ; Hogan et al, 2009 ; Kunnapuu et al, 2021 ; Van Balkom et al, 2002 ).…”