291 General discussion and future perspectives can lead to possibilities of detecting (the absence of) production or degradation biomarkers of collagen type XIV for instance in blood. If these biomarkers can be detected, a next step would be investigating their change throughout the disease prognosis in patients with IPF. A recent proteomics study highlighted differences between IPF and control lung ECM samples but collagen type XIV was not found to be different between IPF and control samples [12]. This is particularly interesting as an earlier mass spectrometry-based proteomics study revealed a 10 times increase in the counts of collagen type XIV in IPF lung tissue compared to control tissue [13]. While my observations and the earlier proteomics study reported by Booth et al. [12] do not fit with proteomics analysis reported by Hoffman et al. [13], the discrepancies between these studies can be explained by different sensitivities of the methods applied. Regardless, these initial observations I made require further mechanistic in vitro and in vivo studies on involvement of collagen type XIV in IPF to understand the role of these lower proportions of collagen type XIV in the altered collagen organization and composition in fibrotic ECM. Investigating fibrotic lung diseases, such as IPF, in vivo and in vitro requires appropriate models that can (partially) mimic the complex nature of these chronic diseases. While in vivo models of fibrosis induced through bleomycin have been frequently used [14], the spontaneous resolution of fibrosis in these models does not properly represent the human disease [15]. Innovative in vitro models derived from patient materials are emerging as an alternative for modeling these diseases: precision lung cut slices, organoids, cell-seeded lung ECM-derived hydrogels and lung-on-chip systems provide a wide range of applications with strengths and limitations within each model system (as reviewed in Chapter 4). Among these models, organoid cultures derived from alveolar epithelial cells isolated from the lungs of patients with IPF was a gap in the literature. In Chapter 5, I described such organoid culture systems for the first time for IPF and compared IPF lung-derived cells to control lung-derived counterparts. I showed that epithelial cells isolated from the lungs of patients with IPF had lower organoid forming capacity compared with those isolated from control donors when supporting cells, which include stromal cells, endothelial cells and macrophages, were present (unfractionated suspensions); however, not in their absence. While the alveolar epithelial cells in IPF have been suggested to become senescent and have reduced regenerative capacity [16], my results showing comparable regenerative capacity of IPF and control lungderived epithelial cells alone were not in concert with these previous reports. On the other hand, when the supporting cells were present, there were differences in the regenerative capacity of IPF epithelial cells compared to control-derived epithelial cells in the organoid cultures. This implies that the reduced regenerative capacity 10
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