Regulation of Fibroblast Phenotype in Lung Fibrosis

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an incurable, fatal disease with increasing incidence and mortality. Despite coordinated attempts to rapidly translate findings from in vitro and preclinical models into improved care, there have been few major therapeutic breakthroughs. The nature of the intercellular communications leading to altered cellular phenotypes in IPF is poorly characterized. We have demonstrated that the cell surface glycoprotein Thy-1 is a fibrosis suppressor which modulates critical aspects of the fibrogenic phenotype in lung fibroblasts. We have found that in response to stress, fibroblasts release membrane-originating extracellular vesicles (EV) containing membrane-bound Thy-1. In bronchial lavage fluid (BALF) from IPF patients, the level of EV-associated Thy-1 correlates with numbers of fibroblastic foci on biopsy, suggesting that Thy-1+ EV may be useful biomarkers of disease activity. In other fields such as cancer and immunology, EV such as exosomes are increasingly appreciated as critical in cell-cell communication; they usually contain non-coding RNA and mRNA that are taken up by recipient cells and alter their phenotypes. Also, EV have been found to be excellent biomarkers in many diseases. Recently, supernatants from mesenchymal stem cells (MSC), which contain EV, have been shown to promote repair of neonatal lung injury, suggesting that EV transmit potent signals relevant to lung injury and repair. Based on these findings, we hypothesize that extracellular vesicles (EV) from activated fibroblasts sustain and amplifiy, whereas MSC- derived EV inhibit, profibrotic cellular phenotypes in pulmonary fibrosis. The following specific aims will test the hypothesis: 1: To define the molecular characteristics of EV released in response to profibrotic stimuli, by characterizing EV released from lung fibroblasts and MSCs in response to fibrogenic stimuli; 2. To define the role of EV in the phenotypic modification of lung cells, by co-culturing fibroblasts and MSC in EV derived from relevant normal and profibrotic cell types, and measuring their uptake and effect on cell phenotype; and 3. To define the role of EV in fibrosis, by characterizing the EV produced in animal models of lung fibrosis and IPF, and by delivering fibroblast- or MSC-derived EV in animal models of fibrosis to determine their fibrogenic and therapeutic effects. Defining the vesiculome relevant to lung fibrosis is critical to understanding and modifying intercellular communication in this pernicious disorder.