Ines Martinez-Corral1, Maria H Ulvmar1, Lukas Stanczuk1, Florence Tatin1, Krishnakumar Kizhatil1, Simon W M John1, Kari Alitalo1, Sagrario Ortega1, Taija Makinen2. 1. From the Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden (I.M.-C., M.H.U., L.S., T.M.); Lymphatic Development Laboratory, Cancer Research UK London Research Institute, London, United Kingdom (I.M.-C., L.S., F.T., T.M.); Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME (K.K., S.W.M.J.); Wihuri Research Institute, Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (K.A.); Biotechnology Programme, Spanish National Cancer Research Centre, Madrid, Spain (S.O.). 2. From the Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden (I.M.-C., M.H.U., L.S., T.M.); Lymphatic Development Laboratory, Cancer Research UK London Research Institute, London, United Kingdom (I.M.-C., L.S., F.T., T.M.); Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME (K.K., S.W.M.J.); Wihuri Research Institute, Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (K.A.); Biotechnology Programme, Spanish National Cancer Research Centre, Madrid, Spain (S.O.). taija.makinen@igp.uu.se.
Abstract
RATIONALE: The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals. OBJECTIVE: We aimed to clarify the origin of the murine dermal lymphatic vasculature. METHODS AND RESULTS: We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous-derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non-Tie2-lineage cells into clusters and vessels through a process defined as lymphvasculogenesis. CONCLUSIONS: Our results demonstrate a significant contribution of nonvenous-derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration.
RATIONALE: The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals. OBJECTIVE: We aimed to clarify the origin of the murine dermal lymphatic vasculature. METHODS AND RESULTS: We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous-derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non-Tie2-lineage cells into clusters and vessels through a process defined as lymphvasculogenesis. CONCLUSIONS: Our results demonstrate a significant contribution of nonvenous-derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration.
Authors: Neil I Bower; Katarzyna Koltowska; Cathy Pichol-Thievend; Isaac Virshup; Scott Paterson; Anne K Lagendijk; Weili Wang; Benjamin W Lindsey; Stephen J Bent; Sungmin Baek; Maria Rondon-Galeano; Daniel G Hurley; Naoki Mochizuki; Cas Simons; Mathias Francois; Christine A Wells; Jan Kaslin; Benjamin M Hogan Journal: Nat Neurosci Date: 2017-05-01 Impact factor: 24.884
Authors: Susan J Doh; Michael Yamakawa; Samuel M Santosa; Mario Montana; Kai Guo; Joseph R Sauer; Nicholas Curran; Kyu-Yeon Han; Charles Yu; Masatsugu Ema; Mark I Rosenblatt; Jin-Hong Chang; Dimitri T Azar Journal: Angiogenesis Date: 2018-07-03 Impact factor: 9.596
Authors: Guy Eelen; Pauline de Zeeuw; Lucas Treps; Ulrike Harjes; Brian W Wong; Peter Carmeliet Journal: Physiol Rev Date: 2018-01-01 Impact factor: 37.312