Key result
In a murine bleomycin lung injury model, pericytes upregulated contractile and secretory markers, while blocking αvβ3 binding in vitro prevented expression of the myofibroblastic marker αSMA.
Why the study?
Prior literature shows pericytes transition into myofibroblasts, but provides limited insight into the molecular cues driving this process during lung injury repair and fibrosis.
In a murine model of bleomycin-induced lung injury, αvβ3 integrin engagement on fibronectin drives pericyte-to-myofibroblast transition, suggesting a potential therapeutic target for pulmonary fibrosis.
May guide pericyte-targeted fibrosis studies in lung injury models; leaves open translational relevance to human disease.
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.
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Hannan et al. (2020) studied Bleomycin-induced lung injury. Bleomycin (in vivo) and cycloRGDfK (in vitro) vs. Controls was evaluated on Pericyte-to-myofibroblast transition (expression of contractile/secretory markers and αSMA). In a murine bleomycin lung injury model, pericytes upregulated contractile and secretory markers, while blocking αvβ3 binding in vitro prevented expression of the myofibroblastic marker αSMA.
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