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Abstract
Cardiac morphogenesis relies on intricate intercellular signaling. Altered signaling impacts cardiac function and is detrimental to embryonic survival. Here we report an unexpected regulatory role of the desmosomal cell adhesion molecule desmoglein 2 (Dsg2) on murine heart development. A large percentage of Dsg2-mutant embryos develop pericardial hemorrhage. Lethal myocardial rupture is occasionally observed, which is not associated with loss of cardiomyocyte contact but with expansion of abnormal, non-myocyte cell clusters within the myocardial wall. Two types of abnormal cell clusters can be distinguished: Type A clusters involve endocard-associated, round-shaped CD31+ cells, which proliferate and invade the myocardium. They acquire Runx1- and CD44-positivity indicating a shift towards a hematopoietic phenotype. Type B clusters expand subepicardially and next to type A clusters. They consist primarily of Ter119+ erythroid cells with interspersed Runx1+/CD44+ cells suggesting that they originate from type A cell clusters. The observed pericardial hemorrhage is caused by migration of erythrocytes from type B clusters through the epicardium and rupture of the altered cardiac wall. Finally, evidence is presented that structural defects of Dsg2-depleted cardiomyocytes are primary to the observed pathogenesis. We propose that cardiomyocyte-driven paracrine signaling, which likely involves Notch1, directs subsequent trans-differentiation of endo- and epicardial cells. Together, our observations uncover a hitherto unknown regulatory role of Dsg2 in cardiogenesis.
Highlights
Cardiac morphogenesis relies on intricate intercellular signaling
We studied the expression of CD44, which is an early marker and regulator of endothelial to hematopoietic transition30. CD44+ cells were almost absent in the wild-type endocardium, myocardium and epicardium of E11.5 embryos and were only rarely detectable in blood (Fig. 5G)
We demonstrate that mutating Dsg[2] unleashes the differentiation capacity of endocardium and possibly epicardium to generate Runx1+ hematopoietic stem cells leading to the formation of massive accumulations of differentiating erythrocytes during mid gestation
Summary
Cardiac morphogenesis relies on intricate intercellular signaling. Altered signaling impacts cardiac function and is detrimental to embryonic survival. Two types of abnormal cell clusters can be distinguished: Type A clusters involve endocard-associated, round-shaped CD31+ cells, which proliferate and invade the myocardium. Histological comparison of wild-type and Dsg2mt/mt embryonic hearts reveals two types of pathological cell clusters and rupture in the mutants. (B–B) The dashed lines delineate two abnormal type A cell clusters in Dsg2mt/mt hearts consisting of densely packed cells that are in continuity with the endocardium. (C–C) depicts a type A cell cluster (dashed line) next to a type B cell cluster (striated line) containing numerous nucleated erythrocytes in the subepicardium of a Dsg2mt/mt heart. (E–E) shows an expanded type B erythrocyte cell cluster (striated line; the empty space is caused by cell loss during tissue processing) in the subepicardium of the right atrium at E12.5 that is directly next to a type A cell cluster (dashed line). Size bars: 100 μm in (A,B,C,E,F,H,I); 150 μm in (D,G); 40 μm in (A,B,C,E,F,H,I) and 60 μm in (D,G)
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