Epicardial Abnormalities and Mesenchymal/Hematopoietic Cell Expansion in Plakophilin 2-Null Mouse Embryonic Hearts

TL;DR

This study shows that a lack of Pkp2 in mouse embryos leads to heart abnormalities and increased blood cell production, suggesting a role in heart development.

Contribution

The study reveals a novel role for Pkp2 in epicardial morphogenesis and its potential link to hematopoietic cell transformation.

Findings

Pkp2 deficiency in mouse embryos results in detached epicardium and accumulation of hematopoietic stem cells.

Epicardial cells in Pkp2-null hearts show altered intermediate filament expression and RUNX1 marker expression.

Deficiencies in Dsg2 and Pkp2 both promote hematopoiesis but affect different cell types in the developing heart.

Abstract

Desmosomal junctions provide structural stability supporting concerted cardiomyocyte contractility. Previously, we demonstrated that a deficiency in the desmosomal transmembrane cadherin desmoglein 2 (Dsg2) reduces desmosome formation and disrupts cardiac morphogenesis, leading to excessive endothelial-to-hematopoietic cell transformation and embryonic lethality. It remained unclear whether this phenotype was specifically driven by Dsg2-deficiency or was a broader consequence of impaired desmosome adhesion. To address this question, we generated Pkp2mt/mt mouse embryos lacking the desmosomal plaque protein Pkp2, which resulted in loss of desmosome formation. Despite the absence of cardiac wall rupture, Pkp2mt/mt and some Pkp2wt/mt presented accumulations of Ter-119+ blood cells and RUNX1+/CD44+ hematopoietic stem cells in the pericardial space. Remarkably, in Pkp2mt/mt hearts, the epicardium was detached from the myocardium, contained rounded cells expressing the hematopoietic stem cell marker RUNX1, and showed altered intermediate filament expression. These findings suggest a potential trans-differentiation of the epicardial cells into hematopoietic cells. In conclusion, deficiencies in both Dsg2 and Pkp2 promote hematopoiesis in the developing murine heart but target different cell types, i.e., endothelial cells, which lack desmosomes, or desmosome-containing epicardial cells. Our results provide evidence for the involvement of Pkp2 in epicardial morphogenesis and remodeling.

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