Fgf10 and epigenetic regulations in lung development and Bronchopulmonary dysplasia

Abstract

Increasing evidence is confirming the key role of FGF10 in lung developmental processes pre- and postnatally as well as in lung regeneration after injury, such like in Bronchopulmonary dysplasia (BPD).With regard to the role of Fgf10 in lung development, we first confirmed using transgenic reporter mouse line that the two transcription factors, ETV4 and ETV5, indeed acted downstream of FGF10/FGFR2b signalling. Further, we showed that FGF10 signalling on distal epithelial progenitors was essential during early lung development and was mainly mediated through beta-catenin/EP300. Paying attention to the lung mesenchyme, we were able to identify and lineage-trace two populations of Fgf10-expressing progenitor cells which gave rise to different mesenchymal cell types pre- and postnatally, e.g. lipofibroblast.In the next chapter, we provided evidence that Fgf10 was crucial for proper development of the alveolar epithelial cells type II (ATII), the pulmonary vasculature and to cope with hyperoxic lung injury using a mouse model for BPD. Pertubation of FGF10/FGFR2b signalling led to a phenotype similar to pulmonary hypertension.During regeneration after naphthalene-mediated epithelial injury, the Yap-Wnt7b-Fgf10 regenerative pathway is activated in the airway smooth muscle cell niche to recruit basal cell to the area of injury. Similarly, we have shown that FGF10/FGFR2b signalling was needed for the regeneration of the alveolar epithelium after bleomycin injury (mouse model of idiopathic pulmonary fibrosis, IPF). Finally, in the last chapter we emphasized the critical role of epigenetic regulations in lung development and BPD. We identified miR-142-3p as a major epigenetic regulator for the proliferation and differentiation of mesenchymal cells and for the alveolar lineage formation during lung development. Also, early exposure to high oxygen levels was associated with persisting changes in histone modifications in pulmonary endothelial cells, which might be accountable for the development of pulmonary hypertension in the pathogenesis of BPD.