119 Dysregulated cross talk between alveolar epithelial cells and stromal cells in IPF reduces epithelial regenerative capacity talk between epithelial cells and other supportive cell populations exists in IPF lungs. In addition to the reduced organoid forming capacity, the organoids derived from IPF lungs were significantly larger compared to non-IPF lung-derived organoids in both unfractionated suspensions and EpCAM+ cell populations. To the best of our knowledge, this is the first report of lower organoid forming capacity in cells isolated from parenchymal tissue of lungs of patients with IPF. Organoid forming efficiency as an indication of regenerative capacity has been demonstrated for several other lung diseases [10]. While fewer numbers of epithelial cells were isolated from the lungs from donors with IPF, our results show reduced numbers of organoids in IPF lung-derived cultures in the unfractionated groups independent of the number of epithelial cells. This was not observed in organoid cultures established from isolated EpCAM+ epithelial cells. This observation does not align with the current school of thought that suggests that the loss of regenerative capacity (specifically their ability to self-renew) of epithelial cells stems from epithelial-mesenchymal transition or senescence in the epithelial cell population in IPF [11]. The comparable organoid forming efficiency seen in isolated EpCAM+ cell populations in IPF and non-IPF groups, relative to the starting number of epithelial cells, indicates that the hampered repair capacity does not result directly from defects in the epithelial progenitor cells. Rather, it may be the result of defective interactions between cells within the stromal niche. However, we did not observe significant differences in the proportions of supporting cell types (stromal, endothelial or macrophage) present in the isolated cell populations between IPF and non-IPF. We did not examine the individual functioning of the cells from the stromal niche, thus it may be that the fibrotic microenvironment in vivo from which these cells were derived has imprinted cells towards different behaviour [12]; the observed differences in organoid supportive capacity might thus result from dysregulated crosstalk between the epithelial cells and stromal cells dictated by the imprinting from the IPF microenvironment. The IPF organoid cultures, both unfractionated and EpCAM+ populations, generated larger organoids compared to non-IPF cultures. This indicates that epithelial progenitors from IPF lungs display intrinsic differences with respect to proliferation or other characteristics that determine organoid size. The morphology of the epithelial cells in tissue sections adjacent to the regions from where we isolated cells from in the lungs of patients with IPF was checked. Previously published reports indicate bronchiolization of the epithelium in the alveolar region in patients with IPF [13], which may be related to the intrinsic differences observed in IPF-derived epithelial cells. When the H&E-stained sections of IPF lung tissue were examined, 5
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