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

Cells, vol. 14, pp. 1751

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.

Authors 9

1. Mistura Dolapo Bolaji Aachen Institute of Molecular and Cellular Anatomy (MOCA)

   RWTH Aachen University

   Affiliation as printed

   Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany

2. P. E. Hartmann

   Maastricht University

   Affiliation as printed

   School of Cardiovascular Disease (CARIM), Faculty of Health, Medicine & Life Sciences (FHML), Maastricht University, Universiteitssingel 50, 6229ER Maastricht, The Netherlands

3. Eva Miriam Buhl Aachen Institute of Pathology Electron Microscopy Facility

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Electron Microscopy Facility, Institute of Pathology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany

4. Robin M. W. Colpaert

   Maastricht University

   Affiliation as printed

   School of Cardiovascular Disease (CARIM), Faculty of Health, Medicine & Life Sciences (FHML), Maastricht University, Universiteitssingel 50, 6229ER Maastricht, The Netherlands

5. Francesca Gasparella

   University of Padua

   Affiliation as printed

   Department of Biology, Padova University, via Ugo Bassi 58B, 35131 Padova, Italy

6. León J. De Windt

   Maastricht University

   Affiliation as printed

   School of Cardiovascular Disease (CARIM), Faculty of Health, Medicine & Life Sciences (FHML), Maastricht University, Universiteitssingel 50, 6229ER Maastricht, The Netherlands

7. Martina Calore

   University of Padua · Maastricht University

   Affiliation as printed

   Department of Biology, Padova University, via Ugo Bassi 58B, 35131 Padova, Italy

   School of Cardiovascular Disease (CARIM), Faculty of Health, Medicine & Life Sciences (FHML), Maastricht University, Universiteitssingel 50, 6229ER Maastricht, The Netherlands

8. Rudolf E. Leube Aachen Institute of Molecular and Cellular Anatomy (MOCA)

   RWTH Aachen University

   Affiliation as printed

   Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany

9. Hoda Moazzen corresponding Aachen Institute of Molecular and Cellular Anatomy (MOCA)

   RWTH Aachen University

   Affiliation as printed

   Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany