title: Angiocrine Bmp2 signaling in murine liver controls normal iron homeostasis.
abstract: Microvascular endothelial cells (ECs) display a high degree of phenotypic and functional heterogeneity among different organs. Organ-specific ECs control their tissue microenvironment by angiocrine factors in health and disease. Liver sinusoidal endothelial cells (LSECs) are uniquely differentiated to fulfill important organ-specific functions in development, under homeostatic conditions, and in regeneration and liver pathology. Recently, Bmp2 has been identified by us as an organ-specific angiokine derived from LSECs. To study angiocrine Bmp2 signaling in the liver, we conditionally deleted Bmp2 in LSECs using EC subtype-specific Stab2-Cre mice. Genetic inactivation of hepatic angiocrine Bmp2 signaling in Stab2-Cre;Bmp2fl/fl(Bmp2LSECKO) mice caused massive iron overload in the liver and increased serum iron levels and iron deposition in several organs similar to classic hereditary hemochromatosis. Iron overload was mediated by decreased hepatic expression of hepcidin, a key regulator of iron homeostasis. Thus, angiocrine Bmp2 signaling within the hepatic vascular niche represents a constitutive pathway indispensable for iron homeostasis in vivo that is nonredundant with Bmp6. Notably, we demonstrate that organ-specific angiocrine signaling is essential not only for the homeostasis of the respective organ but also for the homeostasis of the whole organism.
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Philipp-Sebastian
authors.initials: PS
authors.lastname: Koch
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Victor
authors.identifier: 0000-0001-6083-5534
authors.initials: V
authors.lastname: Olsavszky
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Friederike
authors.initials: F
authors.lastname: Ulbrich
authors.affiliation: Center for Medical Research.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Demory
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Thomas
authors.identifier: 0000-0002-7157-1201
authors.initials: T
authors.lastname: Leibing
authors.affiliation: Institute of Clinical Radiology and Nuclear Medicine.
authors.forename: Thomas
authors.initials: T
authors.lastname: Henzler
authors.affiliation: Institute of Clinical Radiology and Nuclear Medicine.
authors.forename: Mathias
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Johanna
authors.initials: J
authors.lastname: Zierow
authors.affiliation: Institute for Clinical Chemistry, and.
authors.forename: Sven
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Section of Molecular Hepatology, Second Medical Department, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf-Heinlein
authors.affiliation: Section of Molecular Hepatology, Second Medical Department, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Haristi
authors.initials: H
authors.lastname: Gaitantzi
authors.affiliation: Experimental Histopathology Laboratory, The Francis Crick Institute, London, United Kingdom; and.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: Division of Molecular Immunology, and.
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.affiliation: Division of Cellular Immunology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Klapproth
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Kai
authors.identifier: 0000-0002-0107-1674
authors.initials: K
authors.lastname: Schledzewski
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Sergij
authors.identifier: 0000-0002-5718-415X
authors.initials: S
authors.lastname: Goerdt
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology.
authors.forename: Cyrill
authors.initials: C
authors.lastname: Géraud
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000172:deficiency / Q000235:genetics*; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D064451:Hepcidins / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019899:Paracrine Communication; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C525719:Bmp2 protein, mouse; C525817:Bmp6 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D015816:Cell Adhesion Molecules, Neuronal; D064451:Hepcidins; C486733:Stab2 protein, mouse; D007501:Iron; C045073:Cre recombinase; D019426:Integrases