307 English Summary of stromal cells to those formed by epithelial cells alone revealed. These results highlight that the epithelial cells may not be intrinsically defected in IPF, but the negative influence of stromal cells isolated from the fibrotic ECM may be influencing their regenerative capacity in the lungs of patients with IPF. An important aspect of in vitro models is the inclusion of an ECM-mimicking substance. As lung ECM is vital for its functions, these models are required to have proper materials for mimicking the complex composition and/or architecture of lung tissue. Chapter 6 demonstrates utilization of different materials for in vitro models in the context of lung health and disease. The recent advances using such models were summarized as well as the challenges related to using models of different composition and complexity. Chapter 7 builds on the foundation of Chapter 6 and provides a perspective to lung ECM-derived hydrogels as an advanced and innovative tool for mimicking lung microenvironment. These hydrogels are derived from the native lung ECM, retains most of the complex biochemical composition and resembles the mechanical properties of the source tissue. Chapter 8 demonstrates one of the examples for advancing the mimicking capacity of lung ECM-derived hydrogels described in Chapters 4, 6 and 7. While mechanical properties were historically determined by the concentration and the composition of the ECM powder, applying external fiber crosslinking to these hydrogels through a UV/visible range light-triggered reaction revealed that stiffer hydrogels could be produced without altering the biochemical composition. This method, namely Ruthenium crosslinking, was also shown to leave no cytotoxicity in the hydrogels. Increased stiffness, accompanied by altered fiber organization, triggered myofibroblast differentiation in the fibroblasts seeded on top of the crosslinked hydrogels when compared to the untouched hydrogels. This methodology provided a new and cell-friendly manner to alter mechanical properties of the ECM-derived hydrogels for mimicking diseased lung microenvironment in vitro. Another illustration of employing lung ECM-derived hydrogels for advanced in vitro modeling was done in Chapter 9. Hydrogels derived from the decellularized ECM of lungs of IPF and non-IPF donors were seeded with fibroblasts derived from either IPF or non-IPF lungs in a combinatorial manner. While these remodeling responses did not include a detectable change in collagen or glycosaminoglycan content in the hydrogels, collagen fiber organization and mechanical properties of the hydrogels were drastically altered by the fibroblasts seeded in IPF hydrogels due to the instructions provided by the fibrotic ECM, which results in a more pro-fibrotic microenvironment altogether. By characterizing the responses of both types of fibroblasts in both types of microenvironment and comparing the ECM remodeling responses of these
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