Nestin expressing progenitor cells in pulmonary vasculature
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Vascular wall cells distinguished by expression of the neuronal stem cell marker nestin may represent stem cell-like progenitor cells for tissues in various organs. In one of our previous studies, we found that nestin expressing vascular smooth muscle cells and pericytes in testicular blood vessels are the progenitors of testosterone producing Leydig cells. The aim of this study was to investigate nestin expression and nestin+ cells in postnatal and adult lungs.To analyze the expression pattern of nestin and its role as marker for proliferating progenitor cells in the lung, nestin expression and localization was investigated during postnatal development and vascular remodeling in a hypoxia induced pulmonary hypertension model in mice. Nestin data was compared with expression of proliferation markers (PCNA, Ki67) and PDGF receptors. Nestin expression and localization was also investigated in two rat models of pulmonary hypertension, the monocrotaline model and the Su5416/hypoxia model (VEGF receptor-2 blockage by its antagonist Sugen 5416 in combination with hypoxia) as well as in human samples from patients suffering from pulmonary hypertension and pulmonary fibrosis. Nestin was found in a subpopulation of vascular smooth muscle cells in lung vasculature. As compared to adults, significantly higher nestin expression was observed in pulmonary vasculature of postnatal lungs. While investigating the time course of postnatal development, peaks of nestin expression and vascular smooth muscle cell proliferation were found from postnatal day 3 to day 10 that reduced gradually with no nestin and vascular smooth muscle cell proliferation in adults suggesting a strong correlation between nestin expression in and proliferation of vascular smooth muscle cells. Similarly, as compared to normoxic controls, in adult lungs nestin upregulation was found between 3 days and 1 week of hypoxic exposure but not at later time points when pulmonary hypertension became clinically and histologically evident. In hypoxic lungs peak of phosphorylated (activated) PDGF receptor-ß was observed between 4 days and 1 week of hypoxic treatment. Nestin up-regulation correlated well with an increase of cell proliferation and PDGFR-ß phosphorylation/activation.Higher nestin expression was also found in vasculature of lungs from monocrotaline and Su5416/hypoxia treated rat samples. In small arteries, nestin was found in vascular smooth muscle cells. In large arteries of lungs from both rat models, in addition to vascular smooth muscle cells, nestin was also found in cells present in so-called vasculogenic zone at the border of media and adventitia. In the Su5416/hypoxia model, nestin-positive vascular smooth muscle cells were also detected in more complex lesions with neointima, a characteristic feature of this model. Along with arteries, large veins of this model also showed strong nestin immunoreactivity and interestingly, nestin+ cells in these veins were found to be cardiomyocytes.In human samples from patients of pulmonary hypertension, nestin was found in vascular smooth muscle cells in small vessels, in vasculogenic zone in large vessels as well as in vascular lesions e.g. concentric lesions, plexiform lesions and recanalization of thrombosed arteries. In lung samples from patients of pulmonary fibrosis, nestin expression was predominantly found in vascular smooth muscle cells.Certain vascular wall cells capable of proliferation could be identified by nestin expression in lungs and may be used as prognostic and diagnostic markers and new target for therapeutic interventions of diseases like pulmonary hypertension.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler