title: CD146(+) cells are essential for kidney vasculature development.
abstract: The kidney vasculature is critical for renal function, but its developmental assembly mechanisms remain poorly understood and models for studying its assembly dynamics are limited. Here, we tested whether the embryonic kidney contains endothelial cells (ECs) that are heterogeneous with respect to VEGFR2/Flk1/KDR, CD31/PECAM, and CD146/MCAM markers. Tie1Cre;R26R(YFP)-based fate mapping with a time-lapse in embryonic kidney organ culture successfully depicted the dynamics of kidney vasculature development and the correlation of the process with the CD31(+) EC network. Depletion of Tie1(+) or CD31(+) ECs from embryonic kidneys, with either Tie1Cre-induced diphtheria toxin susceptibility or cell surface marker-based sorting in a novel dissociation and reaggregation technology, illustrated substantial EC network regeneration. Depletion of the CD146(+) cells abolished this EC regeneration. Fate mapping of green fluorescent protein (GFP)-marked CD146(+)/CD31(-) cells indicated that they became CD31(+) cells, which took part in EC structures with CD31(+) wild-type ECs. EC network development depends on VEGF signaling, and VEGF and erythropoietin are expressed in the embryonic kidney even in the absence of any external hypoxic stimulus. Thus, the ex vivo embryonic kidney culture models adopted here provided novel ways for targeting renal EC development and demonstrated that CD146(+) cells are critical for kidney vasculature development.
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Center of Excellence in Cell-Extracellular Matrix Research, Oulu, Finland.
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Halt
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Center of Excellence in Cell-Extracellular Matrix Research, Oulu, Finland.
authors.forename: Heikki E
authors.initials: HE
authors.lastname: Pärssinen
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Center of Excellence in Cell-Extracellular Matrix Research, Oulu, Finland.
authors.forename: Sanna M
authors.initials: SM
authors.lastname: Junttila
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Center of Excellence in Cell-Extracellular Matrix Research, Oulu, Finland.
authors.forename: Ulla
authors.initials: U
authors.lastname: Saarela
authors.affiliation: Rangos Research Center, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Sunder
authors.initials: S
authors.lastname: Sims-Lucas
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland.
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Center of Excellence in Cell-Extracellular Matrix Research, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Myllyharju
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Quaggin
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Center of Excellence in Cell-Extracellular Matrix Research, Oulu, Finland.
authors.forename: Ilya N
authors.initials: IN
authors.lastname: Skovorodkin
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, Oulu, Finland; Center of Excellence in Cell-Extracellular Matrix Research, Oulu, Finland; InfoTech Oulu, Oulu, Finland. Electronic address: Seppo.Vainio@oulu.fi.
authors.forename: Seppo J
authors.initials: SJ
authors.lastname: Vainio
mesh_terms: D000818:Animals; D051929:CD146 Antigen / Q000378:metabolism; D002469:Cell Separation; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007668:Kidney / Q000098:blood supply* / Q000166:cytology / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D009924:Organ Culture Techniques; D038081:Organogenesis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051929:CD146 Antigen; C497903:Mcam protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: endothelium; erythropoietin; glomerulus; kidney development; podocyte