title: Fetal liver endothelium regulates the seeding of tissue-resident macrophages.
abstract: Macrophages are required for normal embryogenesis, tissue homeostasis and immunity against microorganisms and tumours. Adult tissue-resident macrophages largely originate from long-lived, self-renewing embryonic precursors and not from haematopoietic stem-cell activity in the bone marrow. Although fate-mapping studies have uncovered a great amount of detail on the origin and kinetics of fetal macrophage development in the yolk sac and liver, the molecules that govern the tissue-specific migration of these cells remain completely unknown. Here we show that an endothelium-specific molecule, plasmalemma vesicle-associated protein (PLVAP), regulates the seeding of fetal monocyte-derived macrophages to tissues in mice. We found that PLVAP-deficient mice have completely normal levels of both yolk-sac- and bone-marrow-derived macrophages, but that fetal liver monocyte-derived macrophage populations were practically missing from tissues. Adult PLVAP-deficient mice show major alterations in macrophage-dependent iron recycling and mammary branching morphogenesis. PLVAP forms diaphragms in the fenestrae of liver sinusoidal endothelium during embryogenesis, interacts with chemoattractants and adhesion molecules and regulates the egress of fetal liver monocytes to the systemic vasculature. Thus, PLVAP selectively controls the exit of macrophage precursors from the fetal liver and, to our knowledge, is the first molecule identified in any organ as regulating the migratory events during embryonic macrophage ontogeny.
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Rantakari
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland.
authors.forename: Norma
authors.initials: N
authors.lastname: Jäppinen
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland.
authors.forename: Emmi
authors.initials: E
authors.lastname: Lokka
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland.
authors.forename: Elias
authors.initials: E
authors.lastname: Mokkala
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Gerke
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, FI-20520, Finland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Peuhu
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, FI-20520, Finland.|Department of Biochemistry, University of Turku, Turku, FI-20500, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland.|Department of Medical Biochemistry and Genetics, University of Turku, Turku, FI-20520, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Elima
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Auvinen
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland.|Department of Medical Microbiology and Immunology, University of Turku, Turku, FI-20520, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D002465:Cell Movement; D004727:Endothelium / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology* / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006706:Homeostasis; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000166:cytology; D009024:Morphogenesis; D039942:Neuropilin-1 / Q000378:metabolism; D009928:Organ Specificity; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015017:Yolk Sac / Q000166:cytology
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C486772:Plvap protein, mouse; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D006493:Heparin; D007501:Iron