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Published on: July 27, 2022
Desmoglein 2 regulates cardiogenesis by restricting hematopoiesis in the developing murine heart
Hoda Moazzen1, Kateryna Venger1, Sebastian Kant1
1Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
Insights
Desmoglein 2 (Dsg2) plays a key role in heart development. Dsg2 mutations cause abnormal cell clusters, leading to embryonic pericardial hemorrhage and cardiac rupture in mice.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Cell Adhesion
Background:
- Cardiac morphogenesis depends on precise intercellular communication.
- Disruptions in signaling pathways can impair heart function and embryonic viability.
- Desmosomal proteins, like desmoglein 2 (Dsg2), are crucial for tissue integrity.
Purpose of the Study:
- To investigate the role of desmoglein 2 (Dsg2) in murine cardiac development.
- To elucidate the mechanisms underlying cardiac abnormalities observed in Dsg2-mutant embryos.
Main Methods:
- Analysis of Dsg2-mutant mouse embryos.
- Histological examination and cell phenotyping (CD31, Runx1, CD44, Ter119).
- Assessment of cardiac wall integrity and cell migration patterns.
Main Results:
- Dsg2-mutant embryos exhibit pericardial hemorrhage and myocardial rupture.
- Abnormal non-myocyte cell clusters (Type A and B) invade the myocardium.
- Type A clusters show a shift towards a hematopoietic phenotype, with Type B clusters containing erythrocytes.
- Hemorrhage results from erythrocyte migration and cardiac wall rupture.
- Dsg2 depletion causes cardiomyocyte structural defects.
Conclusions:
- Desmoglein 2 (Dsg2) has an unexpected regulatory role in heart development.
- Dsg2 deficiency leads to cardiomyocyte defects and abnormal cell cluster formation.
- Cardiomyocyte-derived signaling, potentially via Notch1, influences endo- and epicardial cell differentiation.
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.
