Abstract
Desmogleins (DSG) are a family of cadherin adhesion proteins that were first identified in desmosomes and provide cardiomyocytes and epithelial cells with the junctional stability to tolerate mechanical stress. However, one member of this family, DSG2, is emerging as a protein with additional biological functions on a broader range of cells. Here we reveal that DSG2 is expressed by non-desmosome-forming human endothelial progenitor cells as well as their mature counterparts [endothelial cells (ECs)] in human tissue from healthy individuals and cancer patients. Analysis of normal blood and bone marrow showed that DSG2 is also expressed by CD34+CD45dim hematopoietic progenitor cells. An inability to detect other desmosomal components, i.e., DSG1, DSG3 and desmocollin (DSC)2/3, on these cells supports a solitary role for DSG2 outside of desmosomes. Functionally, we show that CD34+CD45dimDSG2+ progenitor cells are multi-potent and pro-angiogenic in vitro. Using a ‘knockout-first’ approach, we generated a Dsg2 loss-of-function strain of mice (Dsg2lo/lo) and observed that, in response to reduced levels of Dsg2: (i) CD31+ ECs in the pancreas are hypertrophic and exhibit altered morphology, (ii) bone marrow-derived endothelial colony formation is impaired, (iii) ex vivo vascular sprouting from aortic rings is reduced, and (iv) vessel formation in vitro and in vivo is attenuated. Finally, knockdown of DSG2 in a human bone marrow EC line reveals a reduction in an in vitro angiogenesis assay as well as relocalisation of actin and VE-cadherin away from the cell junctions, reduced cell–cell adhesion and increased invasive properties by these cells. In summary, we have identified DSG2 expression in distinct progenitor cell subpopulations and show that, independent from its classical function as a component of desmosomes, this cadherin also plays a critical role in the vasculature.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-016-9520-y) contains supplementary material, which is available to authorized users.
Highlights
Desmoglein-2 (DSG2), a type 1 transmembrane protein belonging to the cadherin family, is an adhesion molecule with well-described functions in the formation of cell–cell adhesion complexes called desmosomes
In a global comparative gene expression analysis of human umbilical cord blood (UCB)-derived CD133?CD34?VEGFR2? non-adherent endothelial progenitor cells (EPCs) and donor matched human umbilical vein endothelial cells (HUVEC), we identified DSG2 to be significantly elevated in EPCs (NCBI Gene Expression Omnibus (GEO) Accession number GSE25979) [22]
Validation by qRT-PCR in additional donors confirmed that EPCs express *180-fold more DSG2 mRNA when compared to HUVEC (Fig. 1a)
Summary
Desmoglein-2 (DSG2), a type 1 transmembrane protein belonging to the cadherin family, is an adhesion molecule with well-described functions in the formation of cell–cell adhesion complexes called desmosomes. The desmosome is a specialised junction that provides intercellular links giving tensile strength to tissues that experience mechanical stress, such as in the myocardium, skin and gastrointestinal mucosa [1,2,3]. In keeping with its role in tissue integrity, loss of DSG2 function in humans is directly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal recessive disease underpinned by myocyte apoptosis and fibrous degeneration of the myocardium [5, 6]
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