title: Nestin-expressing vascular wall cells drive development of pulmonary hypertension.
abstract: Nestin, a well-known marker of neuronal stem cells, was recently suggested to characterise stem cell-like progenitors in non-neuronal structures during development and tissue repair. Integrating novel morphological approaches (CLARITY), we investigate whether nestin expression defines the proliferating cell population that essentially drives vascular remodelling during development of pulmonary hypertension.The role of nestin was investigated in lungs of nestin-GFP (green fluorescent protein) mice, models of pulmonary hypertension (rat: monocrotaline, SU5416/hypoxia; mouse: hypoxia), samples from pulmonary hypertension patients and human pulmonary vascular smooth muscle cells (VSMCs).Nestin was solely found in lung vasculature and localised to proliferating VSMCs, but not bronchial smooth muscle cells. Nestin was shown to affect cell number and was significantly enhanced in lungs early during development of pulmonary hypertension, correlating well with increased VSMC proliferation, expression of phosphorylated (activated) platelet-derived growth factor receptor β and downregulation of the smooth muscle cell differentiation marker calponin. At later time points when pulmonary hypertension became clinically evident, nestin expression and proliferation returned to control levels. Increase of nestin-positive VSMCs was also found in human pulmonary hypertension, both in vessel media and neointima.Nestin expression seems to be obligatory for VSMC proliferation, and specifies lung vascular wall cells that drive remodelling and (re-)generation. Our data promise novel diagnostic tools and therapeutic targets for pulmonary hypertension.
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany These authors contributed equally.
authors.forename: Farhan
authors.initials: F
authors.lastname: Saboor
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany These authors contributed equally.
authors.forename: Ansgar N
authors.initials: AN
authors.lastname: Reckmann
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany These authors contributed equally.
authors.forename: Claudia U M
authors.initials: CU
authors.lastname: Tomczyk
authors.affiliation: University of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Systems (ECCPS), Dept of Internal Medicine, Members of the German Center for Lung Research, Justus-Liebig-University, Giessen, Germany.
authors.forename: Dorothea M
authors.initials: DM
authors.lastname: Peters
authors.affiliation: University of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Systems (ECCPS), Dept of Internal Medicine, Members of the German Center for Lung Research, Justus-Liebig-University, Giessen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Kaschtanow
authors.affiliation: University of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Systems (ECCPS), Dept of Internal Medicine, Members of the German Center for Lung Research, Justus-Liebig-University, Giessen, Germany.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA Center for Developmental Genetics and Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA NBIC, Moscow Institute of Physics and Technology, Moscow, Russia.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Michurina
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA Center for Developmental Genetics and Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA NBIC, Moscow Institute of Physics and Technology, Moscow, Russia.
authors.forename: Grigori
authors.initials: G
authors.lastname: Enikolopov
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Müller
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mietens
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany ralf.middendorff@anatomie.med.uni-giessen.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Middendorff
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000032:analysis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D064231:Nestin / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D066253:Vascular Remodeling; D000096985:Calponins
chemical_list: D002135:Calcium-Binding Proteins; D049452:Green Fluorescent Proteins; D008840:Microfilament Proteins; D016686:Monocrotaline; D064231:Nestin; D020797:Receptor, Platelet-Derived Growth Factor beta; D000096985:Calponins