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Idiopathic pulmonary fibrosis is an interstitial lung disease whose prevalence increases after age 55. Using the surfactant protein C (Sftpc) murine model of lung fibrosis, we have previously demonstrated that stress in aged alveolar type II cells (AT2s) results in increased lung fibrosis as compared to younger mice. Recently reported is the emergence of an injury associated transitional fibroblast preceding the profibrotic pathological Cthrc1 fibroblast. Leveraging these findings and our aged PF model, we sought to characterize the role of this transitional fibroblast in profibrotic crosstalk. Administration of tamoxifen to SftpcI73T mice, induces expression of mutant protein and promotes alveolitis followed by fibrogenesis. Flow cytometry, single cell sequencing, and population RNA sequencing were used to characterize the alveolar niche followed by in-vitro organoid modeling with young or aged AT2s and transitional AT2s in combination with fibroblast subpopulations. In aged mice we observed increased inflammation, increased AT2 transitional cells, and more mortality. Organoids with AT2I73T or transitional AT2s and bulk fibroblasts yielded a decreased colony forming efficiency with formed organoids significantly larger in size independent of AT2 age. Application of fibroblast subpopulations in organoid assays demonstrate that both adventitial and transitional fibroblasts support organoid formation in AT2WT and AT2I73T organoids which was lost by replacement with aged fibroblasts. These data suggest that aberrant alveolar niche signaling can emerge through age associated changes to mesenchyme subpopulations or persistence of AT2 transitional states.
Rodríguez et al. (Fri,) studied this question.