Extracellular Matrix Remodeling Associated with Bleomycin-Induced Lung Injury Supports Pericyte-To-Myofibroblast Transition
| Autor: | Thomas H. Barker, Catherine Sano, Andrew E. Miller, Riley T. Hannan, Ruei-Chun Hung, Shayn M. Peirce |
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| Rok vydání: | 2020 |
| Předmět: |
Histology
QH301-705.5 Integrin Biophysics Lung injury Biochemistry Article Extracellular matrix Bleomycin Fibrosis Genetics medicine Biology (General) Molecular Biology Pericyte Myofibroblast biology Chemistry Cell Biology SMC Smooth muscle cell medicine.disease ECM extracellular matrix Cell biology Fibronectin medicine.anatomical_structure αSMA Alpha smooth muscle actin Differentiation biology.protein CD146 |
| Zdroj: | Matrix Biology Plus, Vol 10, Iss, Pp 100056-(2021) Matrix Biology Plus |
| Popis: | Of the many origins of pulmonary myofibroblasts, microvascular pericytes are a known source. Prior literature has established the ability of pericytes to transition into myofibroblasts, but provide limited insight into molecular cues that drive this process during lung injury repair and fibrosis. Fibronectin and RGD-binding integrins have long been considered pro-fibrotic factors in myofibroblast biology, and here we test the hypothesis that these known myofibroblast cues coordinate pericyte-to-myofibroblast transitions. Specifically, we hypothesized that αvβ3 integrin engagement on fibronectin induces pericyte transition into myofibroblastic phenotypes in the murine bleomycin lung injury model. Myosin Heavy Chain 11 (Myh11)-CreERT2 lineage tracing in transgenic mice allows identification of cells of pericyte origin and provides a robust tool for isolating pericytes from tissues for further evaluation. We used this murine model to track and characterize pericyte behaviors during tissue repair. The majority of Myh11 lineage-positive cells are positive for the pericyte surface markers, PDGFRβ (55%) and CD146 (69%), and display typical pericyte morphology with spatial apposition to microvascular networks. After intratracheal bleomycin treatment of mice, Myh11 lineage-positive cells showed significantly increased contractile and secretory markers, as well as αv integrin expression. According to RNASeq measurements, many disease and tissue-remodeling genesets were upregulated in Myh11 lineage-positive cells in response to bleomycin-induced lung injury. In vitro, blocking αvβ3 binding through cycloRGDfK prevented expression of the myofibroblastic marker αSMA relative to controls. In response to RGD-containing provisional matrix proteins present in lung injury, pericytes may alter their integrin profile. Highlights • Pericyte lineage model enables study of transdifferentiating pericytes. • High dimensional flow cytometry used to characterize pulmonary stromal cells • Pulmonary pericytes express matrix-remodeling genes and proteins in lung injury. • Myofibroblasts derived from pericytes have active αvβ3 integrin. • In vitro assay reveals necessity of RGD for pericyte transdifferentiation. |
| Databáze: | OpenAIRE |
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