Fibroblast Growth factor signaling in lipofibroblast formation and transdifferentiation during normal lung development and fibrosis

点击翻译按钮获取中文摘要

In this proposal, we will test the overall hypothesis that a growth factor called Fibroblast Growth factor 10 (FGF10) controls the commitment of lipofibroblast progenitors into the lipofibroblast lineage during lung development and prevents the transdifferentiation of lipofibroblasts to activated myofibroblast during lung fibrosis. We will use a recently developed mouse strain where Cre-ERT2 is under the control of endogenous Fgf10 regulatory sequences (this new mouse line is called Fgf10Cre-ERT2) to demonstrate that a specific cell population located in the mesenchyme and expressing Fgf10 during the pseudoglandular stage (E11.5-E16) contains the progenitors for the lipofibroblasts at late fetal/early post natal stages (E18.5-P5). We will also determine the potential functional role played by an autocrine FGF10 signaling loop in the mesenchyme in controlling the differentiation of these early mesenchymal progenitors to the lipofibroblast lineage. Additionally, we will use the Fgf10Cre-ERT2 line to determine whether these Fgf10-positive progenitor cells can give rise to activated myofibroblasts in the lung in several experimental models of lung fibrosis. We will test also if overexpression of Fgf10 prevents the formation of activated myofibroblasts in these models of lung fibrosis. Finally, we will validate our observations made in mice by carrying a more translational approach. We will take advantage of the Biobank for human material (IPF versus donor) at Justus Liebig University in Giessen to determine the expression of FGF ligands, their receptors and associated downstream targets as well as lipofibroblast markers. We will also use primary culture of interstitial fibroblasts from IPF versus donors and quantify the expression of these genes by qPCR as well as monitor their in vitro response to different growth factors treatments including FGF10.