Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition
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. Fi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Matrix Biology Plus |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590028520300375 |
| _version_ | 1819098175654330368 |
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| author | Riley T. Hannan Andrew E. Miller Ruei-Chun Hung Catherine Sano Shayn M. Peirce Thomas H. Barker |
| author_facet | Riley T. Hannan Andrew E. Miller Ruei-Chun Hung Catherine Sano Shayn M. Peirce Thomas H. Barker |
| author_sort | Riley T. Hannan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T00:26:49Z |
| format | Article |
| id | doaj.art-984d829f2e7e42fd9c3af50c4aad6a22 |
| institution | Directory Open Access Journal |
| issn | 2590-0285 |
| language | English |
| last_indexed | 2024-12-22T00:26:49Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Matrix Biology Plus |
| spelling | doaj.art-984d829f2e7e42fd9c3af50c4aad6a222022-12-21T18:45:02ZengElsevierMatrix Biology Plus2590-02852021-06-0110100056Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transitionRiley T. Hannan0Andrew E. Miller1Ruei-Chun Hung2Catherine Sano3Shayn M. Peirce4Thomas H. Barker5Department of Pathology, University of Virginia, 415 Lane Road, Charlottesville, VA, United StatesDepartment of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA, United StatesDepartment of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA, United StatesDepartment of Chemical Engineering, University of Virginia, 102 Engineer's Way, Charlottesville, VA, United StatesDepartment of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA, United StatesDepartment of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA, United States; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2590028520300375PericyteDifferentiationBleomycinIntegrinMyofibroblast |
| spellingShingle | Riley T. Hannan Andrew E. Miller Ruei-Chun Hung Catherine Sano Shayn M. Peirce Thomas H. Barker Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition Matrix Biology Plus Pericyte Differentiation Bleomycin Integrin Myofibroblast |
| title | Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition |
| title_full | Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition |
| title_fullStr | Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition |
| title_full_unstemmed | Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition |
| title_short | Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition |
| title_sort | extracellular matrix remodeling associated with bleomycin induced lung injury supports pericyte to myofibroblast transition |
| topic | Pericyte Differentiation Bleomycin Integrin Myofibroblast |
| url | http://www.sciencedirect.com/science/article/pii/S2590028520300375 |
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