Cross-Talk Between Inflammation and Fibroblast Growth Factor 10 During Organogenesis and Pathogenesis: Lessons Learnt From the Lung and Other Organs

The adult human lung is constantly exposed to irritants like particulate matter, toxic chemical compounds, and biological agents (bacteria and viruses) present in the external environment. During breathing, these irritants travel through the bronchi and bronchioles to reach the deeper lung containing the alveoli, which constitute the minimal functional respiratory units. The local biological responses in the alveoli that follow introduction of irritants need to be tightly controlled in order to prevent a massive inflammatory response leading to loss of respiratory function. Cells, cytokines, chemokines and growth factors intervene collectively to re-establish tissue homeostasis, fight the aggression and replace the apoptotic/necrotic cells with healthy cells through proliferation and/or differentiation. Among the important growth factors at play during inflammation, members of the fibroblast growth factor (Fgf) family regulate the repair process. Fgf10 is known to be a key factor for organ morphogenesis and disease. Inflammation is influenced by Fgf10 but can also impact Fgf10 expression per se. Unfortunately, the connection between Fgf10 and inflammation in organogenesis and disease remains unclear. The aim of this review is to highlight the reported players between Fgf10 and inflammation with a focus on the lung and to propose new avenues of research.

Characterization of a novel Fgf10CreERT2 knock-in mouse line targeting postnatal lung Fgf10 lineages

Fgf10 is a key gene during development, homeostasis and repair after injury. We previously reported a Fgf10CreERT2 line (with the CreERT2 cassette inserted in frame with the start codon of exon 1), called thereafter Fgf10Ki-v1, to target Fgf10Pos cells. While this line allowed fairly efficient and specific labeling of Fgf10Pos cells during the embryonic stage, it failed to target these cells after birth, particularly in the postnatal lung, which has been the focus on our research. We report here the generation and validation of a new Fgf10CreERT2 (called thereafter Fgf10Ki-v2) with the insertion of the expression cassette in frame with the stop codon of exon 3. This new Fgf10Ki-v2 line exhibited comparable Fgf10 expression level to their wild type counterpart. However, a disconnection between the Fgf10 and the Cre expression was observed in Fgf10Ki-v2/+ lungs. In addition, lung and limb agenesis were observed in homozygous embryos suggesting a loss of Fgf10 functional allele in Fgf10Ki-v2 mice. Bio-informatics analysis shows that the 3’UTR, where the CreERT2 cassette is inserted, contains numerous putative transcription factor binding sites. By crossing this line with tdTomato reporter line, we demonstrated that tdTomato expression faithfully recapitulated Fgf10 expression during development. Significantly, Fgf10Ki-v2 mouse is capable of significantly targeting Fgf10Pos cells in the adult lung. Therefore, despite the aforementioned limitations, this new Fgf10Ki-v2 line opens the way for future mechanistic experiments involving the postnatal lung.