FGF10 belongs to a family of evolutionary-conserved peptides that are involved in embryonic organogenesis as well as postnatal homeostasis. During embryonic lung development, Fgf10-expressing cells define the domain for directional growth of epithelial buds and thus orchestrate branching morphogenesis. Disruption of FGF10 signaling not only leads to failure in branching but also to malformation of various mesenchymal lineages. Here, we generated a knock-in mouse line that allows lineage tracing of Fgf10-expressing cells during development and postnatally in a time-controlled manner.Our validation studies show that: The Fgf10iCre knock-in line faithfully reports Fgf10 expression in many organs and tissues during embryonic development The insertion of Cre-ERT2 cassette in exon 1 led to the deletion of intronic sequences that are critical for the maintenance of Fgf10 expression over time. In spite of that, prolonged tamoxifen exposure enables the labeling of a considerable number of Fgf10-expressing cells in the postnatal lung.Our findings from the lineage-tracing studies demonstrate that: Fgf10-expressing cells are potent mesenchymal progenitors in vivo Fgf10-expressing cells from early lung development give rise to parabronchial and vascular smooth muscle cells as well aslipofibroblasts during late development Fgf10-expressing cells from late lung development and postnatally areprecursors for lipofibroblasts rather than alveolar myofibroblasts During adult life, these cells represent a subpopulation of residentMSCs that, upon bleomycin injury, give rise to activated myofibroblasts Recombinant FGF10 is capable of acting on mesenchymal cells to induce the lipofibroblast phenotype Our findings suggest that these cells can be a potential target for treating lung fibrosis in humans.Thus, we propose a model in which Fgf10-expressing cells represent a population of resident mesenchymal stem cells that reside in the adult lung. Under homeostatic conditions, these cells give rise to lipofibroblasts. Injury to AEC II leads to a decrease in PTHrP/PPARgamma signaling and increase in TGF-beta and Wnt signaling, leading to their transdifferentiation to activated myofibroblasts.
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