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Note: thesis: Thesis (Ph. D.)--Brown University, 2020
Genre (aat): theses
Abstract: Abstract of ``Characterization of 2D and 3D Models of Particle-Induced Fibrogenesis'' by Alysha E. Simmons, Ph.D., Brown University, October 2020 Pulmonary fibrosis is a chronic, progressive lung disease that destroys pulmonary architecture due to dysregulated wound healing. With thousands of untested engineered nanomaterials being manufactured annually, there is a need for high-throughput screening tools to predict the adverse human health impacts of inhaled nanomaterials at environmentally relevant concentrations. Previous toxicity testing paradigms can be inadequate to resolve single-cell heterogeneity in cell populations driven by single-cell response to deposited, insoluble nanomaterials. In order to address this need, we developed several 2D and 3D models capable of measuring the fibrotic potential of a panel of nanomaterials benchmarked to human case studies of fibrogenic crocidolite asbestos and non-toxic carbon black exposure and rodent studies of fibrogenic carbon nanotubes. This thesis work evaluates the effects of substrate and nanoparticle exposures to drive fibroblast to myofibroblast differentiation in a lung fibroblast cell line using single-cell and multivariate analysis techniques. Each model incorporates human lung fibroblasts and a marker of myofibroblast differentiation, the cell responsible for the destruction of the lung architecture during fibrosis. First, fibroblast culture on soft substrates reveals sensitivity to nanomaterial exposure detected by single-cell quantification of biomarker and cytoskeletal features. Second, preliminary work characterizes multicellular interactions inside non-adherent, 3D microtissues to model the effects of lung fibroblast and bronchial epithelial cell or macrophage coculture on cell-cell and cell-particle interactions that we hypothesize occur within fibroblastic foci. Fibroblast and epithelial cell coculture microtissues are viable models for acute toxicity endpoints, are predominantly comprised of myofibroblasts and mesenchymal-epithelial cells, exhibit sequestration of nanomaterial exposures into discrete foci, and deposit low levels of nascent ECM. Additional preliminary results characterize fibroblast and macrophage coculture microtissues meant to assess the effects of particle exposure on TGF-$\beta$ signaling pathway activation by fibroblast-macrophage cadherin-11-driven interactions. Overall, non-soluble, biopersistent particle exposures are difficult to evaluate due to the limitations of current 2D model systems and the prohibitive cost and time commitment of rodent models. The application of 2D single-cell multivariable analysis and 3D microtissue models offer opportunities to develop sensitive screening tools that are cost-effective and readily available for use in academic and regulatory settings.
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Type of Resource (primo): dissertations