306 Appendices ENGLISH SUMMARY Lung fibrosis includes a group of devastating rare diseases with poor prognosis and very low survival rates. Among these, idiopathic pulmonary fibrosis (IPF) is the most common form although its origin is poorly understood. Deposition of the excessive extracellular matrix (ECM) by the recruited (myo)fibroblasts due to an abnormal wound repair mechanism originating from the epithelial cells is currently thought to be central theme of the disease. This fibrotic ECM can exert its influence through its aberrant composition, altered biomechanics or disorganized fibers to guide cells towards abnormal behavior. Therefore, this thesis aimed to investigate the interactions between the fibrotic ECM and the cells in the context of the perpetuation of the (pro-)fibrotic responses. Chapter 2 outlines the changes in lung ECM in lung fibrosis with respect to its biochemical and biomechanical properties as well as topography. After summarizing how resident cell-driven pro-fibrotic responses can be caused by different properties of the fibrotic ECM, an updated landscape of the involvement of ECM-degrading enzymes and degradation products from ECM proteins is also given. Building on this knowledge, Chapter 3 explored how one of the less well-investigated collagens, collagen type XIV, is involved in IPF. While it was known that collagen type XIV, supports collagen fibril organization, its status with respect to its amount and localization was not demonstrated before. Transcriptomics analysis on publicly available datasets revealed an increase in COL14A1 gene, which codes the collagen type XIV protein, in fibroblasts and myofibroblasts. When the stained sections of IPF lungs were analyzed digitally, a lower proportional area for collagen type XIV was found for both whole tissue and specific tissue compartments such as airway wall or parenchyma. These consistently lower proportions of collagen type XIV may have implications for the assembly of the ECM fibers which may contribute to progression of fibrosis. The importance of different methods of recreating lung microenvironment in threedimensional (3D) composes of the main message of Chapter 4, in which different state-of-the-art in vitro models were discussed with respect to their advantages, disadvantages and challenges associated with them. These model systems, namely precision cut lung slices, lung organoids, (cell-seeded) lung ECM-derived hydrogels and lung-on-chip systems, provide exciting opportunities to mimic lung in vitro. Chapter 5 includes one of such models, lung organoids, to explore the regenerative responses of the epithelial cells isolated from lungs of patients with IPF. Comparison of the number and the size of organoids formed by the epithelial cells in the presence
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