13 General Introduction In Chapter 7, I provided a perspective on recent developments in lung ECM-derived hydrogels. After a brief review of the innovative science utilizing such hydrogels, I deliberated on the path towards developing new technologies based on ECM-derived hydrogels. In Chapter 8, I harnessed the potential of lung ECM-derived hydrogels by artificially introducing fiber crosslinking. I hypothesized that applying additional fiber crosslinking would result in increased stiffness, and in turn would trigger cellular changes that are also observed during the fibrosis process. I investigated the changes in hydrogel mechanics and fiber organization, and examined cellular responses with respect to fibroblast activation. By creating an in vitro model that represents changes in the mechanical properties of fibrotic ECM alone, I succeeded in separating the mechanical influence of fibrotic ECM from the biomechanical influence on cells. In Chapter 9, I examined ECM and cell interactions using both IPF and non-IPF human lung ECM-derived hydrogels and human primary lung fibroblasts. I hypothesized that the origin of microenvironment would overrule the origin of the fibroblasts, and that IPF matrix can drive fibrotic responses in fibroblasts from normal lungs. I tested this hypothesis by comparing the influence of the microenvironment with the influence of the cell origin by combining IPF or non-IPF ECM-derived hydrogels with IPF or nonIPF fibroblasts, ultimately resulting in a combinatorial comparison. I characterized changes in collagen amount and collagen fiber organization, glycosaminoglycan content as well as mechanical properties of hydrogels with and without fibroblasts to compare the instructiveness of non-IPF and IPF microenvironments. In Chapter 10, the outcomes of the individual chapters of this thesis are integrated and discussed. The future perspectives of our findings with respect to interactions between ECM and cells in IPF are also included in this discussion. In the context of cellular functions, mechanical forces and fibrillar organization, this section concludes with how ECM brings them all, binds them all, and ultimately, rules them all. 1
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