Extracellular Matrix Remodeling Associated with Bleomycin-Induced Lung Injury Supports Pericyte-To-Myofibroblast Transition

摘要: Of the many origins of pulmonary myofibroblasts, microvascular pericytes are a known source. Prior literature has established ability to transition into but provide limited insight molecular cues that drive this process during lung injury repair and fibrosis. Fibronectin RGD-binding integrins have long been considered pro-fibrotic factors in myofibroblast biology, here we test hypothesis these coordinate pericyte-to-myofibroblast transitions. Specifically, hypothesized v{beta}3 integrin engagement on fibronectin induces pericyte myofibroblastic phenotypes murine bleomycin model. Myosin Heavy Chain 11 (Myh11)-CreERT2 lineage tracing transgenic mice allows identification cells origin provides robust tool for isolating from tissues further evaluation. We used model track characterize behaviors tissue repair. The majority Myh11 lineage-positive positive surface markers, PDGFR{beta} (55%) CD146 (69%), display typical morphology with spatial apposition networks. After intratracheal treatment mice, showed significantly increased contractile secretory as well v expression. According RNASeq measurements, disease tissue-remodeling genesets were upregulated response bleomycin-induced injury. In vitro, blocking binding through cyclo-RGDfK prevented expression marker SMA relative controls. RGD-containing provisional matrix proteins present injury, may alter their profile. This altered matrix-integrin axis contributes pericyte-to-myofibroblastic represents possible therapeutic target limiting burden HighlightsO_LIPericyte enables study transdifferentiating C_LIO_LIHigh dimensional flow cytometry stromal C_LIO_LIPulmonary express matrix-remodeling genes C_LIO_LIMyofibroblasts derived active C_LIO_LIIn vitro assay reveals necessity RGD transdifferentiation C_LI