Author:
Saboor Farhan,Reckmann Ansgar N.,Tomczyk Claudia U.M.,Peters Dorothea M.,Weissmann Norbert,Kaschtanow Andre,Schermuly Ralph T.,Michurina Tatyana V.,Enikolopov Grigori,Müller Dieter,Mietens Andrea,Middendorff Ralf
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.
Funder
University Medical Center Giessen and Marburg
U.S. Department of Health and Human Services
Ministry of Education and Science of the Russian Federation
Deutsche Forschungsgemeinschaft
Excellence Cluster Cardio Pulmonary System
German Lung Center
LOEWE Programme of the State Hesse
Publisher
European Respiratory Society (ERS)
Subject
Pulmonary and Respiratory Medicine
Cited by
32 articles.
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