title: A non-canonical role for desmoglein-2 in endothelial cells: implications for neoangiogenesis.
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(+)CD45(dim) 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(+)CD45(dim)DSG2(+) 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 (Dsg2 (lo/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.
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ebert
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: Lih Y
authors.initials: LY
authors.lastname: Tan
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: M Zahied
authors.initials: MZ
authors.lastname: Johan
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: Kay Khine Myo
authors.initials: KK
authors.lastname: Min
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: Michaelia P
authors.initials: MP
authors.lastname: Cockshell
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: Kate A
authors.initials: KA
authors.lastname: Parham
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Betterman
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Paceman
authors.initials: P
authors.lastname: Szeto
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Samantha
authors.initials: S
authors.lastname: Boyle
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Lokugan
authors.initials: L
authors.lastname: Silva
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Peng
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: YouFang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ruszkiewicz
authors.affiliation: South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.affiliation: South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
authors.affiliation: South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Koblar
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Harvey
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia.|Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 14, Rundle Mall, Adelaide, SA, 5000, Australia. claudine.bonder@unisa.edu.au.|Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia. claudine.bonder@unisa.edu.au.
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Bonder
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D051301:Desmoglein 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C495314:DSG2 protein, human; D051301:Desmoglein 2; C495315:Dsg2 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: DESMOGLEIN-2; Endothelial progenitor cells; Endothelium; Hematopoietic stem and progenitor cells; Mouse models of neoangiogenesis