cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels
Lukas Stanczuk,
Ines Martinez-Corral,
Maria H. Ulvmar,
Yang Zhang,
Bàrbara Laviña,
Marcus Fruttiger,
Ralf H. Adams,
Dieter Saur,
Christer Betsholtz,
Sagrario Ortega,
Kari Alitalo,
Mariona Graupera,
Taija Mäkinen
Affiliations
Lukas Stanczuk
The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden
Ines Martinez-Corral
The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden
Maria H. Ulvmar
The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden
Yang Zhang
The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden
Bàrbara Laviña
The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden
Marcus Fruttiger
UCL Institute of Ophthalmology, University College London (UCL), 11-43 Bath Street, London EC1V 9EL, UK
Ralf H. Adams
Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, and Faculty of Medicine, University of Münster, 48149 Münster, Germany
Dieter Saur
Department of Internal Medicine 2, Klinikum Rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany
Christer Betsholtz
The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden
Sagrario Ortega
Biotechnology Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029 Madrid, Spain
Kari Alitalo
Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
Mariona Graupera
Vascular Signalling Lab, IDIBELL, 3a planta - Gran Via de l’Hospitalet 199, L’Hospitalet de Llobregat, 08908 Barcelona, Spain
Taija Mäkinen
The Beijer Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjöldsväg 20, 752 85 Uppsala, Sweden
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.
