Figure 8. Role of PGF_2α as a driver of fibroblast heterogeneity in pulmonary fibrosis.

Application of single-cell discovery and in vitro validation identifies PGF_2α as a driver of adventitial fibroblast activation into the transitional fibroblast state. Paired with work by Tsukui et al. demonstrating potential of alveolar (lipo) fibroblasts to enter the same transitional state through IL-1B stimulation (23), there is now evidence for differential drivers of transitional fibroblast differentiation within fibroblast population subsets. Concurrently, classical profibrotic TGF-β signaling drives entry of adventitial and alveolar fibroblasts as an “override” into a terminally activated fibroblast state expressing Cthrc1. Contextualizing these findings with previous work by Oga et al. (32) suggests that PGF_2α-stimulated transitional fibroblast may be more sensitive to a second hit (e.g., TGF-β, PDGF, or CTGF), accelerating the expansion of the terminal fibrotic fibroblast population.