title: cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels.
abstract: Pathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110α PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.
authors.affiliation: The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden; Lymphatic Development Laboratory, Cancer Research UK London Research Institute (LRI), 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Lukas
authors.initials: L
authors.lastname: Stanczuk
authors.affiliation: The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden; Lymphatic Development Laboratory, Cancer Research UK London Research Institute (LRI), 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Ines
authors.initials: I
authors.lastname: Martinez-Corral
authors.affiliation: The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Ulvmar
authors.affiliation: The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden.
authors.forename: Bàrbara
authors.initials: B
authors.lastname: Laviña
authors.affiliation: UCL Institute of Ophthalmology, University College London (UCL), 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.affiliation: Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, and Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Department of Internal Medicine 2, Klinikum Rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden; Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles Väg 2, 171 77 Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Biotechnology Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Vascular Signalling Lab, IDIBELL, 3a planta - Gran Via de l'Hospitalet 199, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.affiliation: The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden; Lymphatic Development Laboratory, Cancer Research UK London Research Institute (LRI), 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Electronic address: taija.makinen@igp.uu.se.
authors.forename: Taija
authors.initials: T
authors.lastname: Mäkinen