FGF10 Triggers De Novo Alveologenesis in a Bronchopulmonary Dysplasia Model: Impact on Resident Mesenchymal Niche Cells

Abstract

Bronchopulmonary dysplasia (BPD) is a neonatal lung disease developing in premature babies characterized by arrested alveologenesis and associated with decreased Fibroblast growth factor 10 (FGF10) expression. One-week hyperoxia (HYX) exposure of newborn mice leads to a permanent arrest in alveologenesis. To test the role of Fgf10 signaling to promote de novo alveologenesis following hyperoxia, we used transgenic mice allowing inducible expression of Fgf10 and recombinant FGF10 (rFGF10) protein delivered intraperitoneally. We carried out morphometry analysis, and IF on day 45. Alveolospheres assays were performed co-culturing AT2s from normoxia (NOX) with FACS-isolated Sca1 Pos resident mesenchymal cells (rMC) from animals exposed to NOX, HYX-PBS, or HYX-FGF10. scRNAseq between rMC-Sca1 Pos isolated from NOX and HYX-PBS were also carried out. Transgenic overexpression of Fgf10 and rFGF10 administration rescued the alveologenesis defects following HYX. Alveolosphere assays indicate that the activity of rMC-Sca1 Pos is negatively impacted by HYX and partially rescued by rFGF10 treatment. Analysis by IF demonstrates a significant impact of rFGF10 on the activity of resident mesenchymal cells. scRNAseq results identified clusters expressing Fgf10, Fgf7, Pdgfra, and Axin2, which could represent the rMC niche cells for the AT2 stem cells. In conclusion, we demonstrate that rFGF10 administration is able to induce de novo alveologenesis in a BPD mouse model and identified subpopulations of rMC-Sca1 Pos niche cells potentially representing its cellular target.

Phenotypic spectrum of FGF10-related disorders: a systematic review

“…This may represent an additional feature of the BPD ( Chao et al, 2019 ). However, a recent study showed that overexpression of Fgf10 and administration of rFGF10 rescued alveologenesis defects in transgenic mice ( Taghizadeh et al, 2022 ).…”

Insights into the Black Box of Intra-Amniotic Infection and Its Impact on the Premature Lung: From Clinical and Preclinical Perspectives

“…FGF10 is synthesized by submesothelial cells and binds to fibroblast growth factor receptor 2b (FGFR2B), which was shown to be regulated by TLR2/4-NFKB signaling [ 121 ]. Reduced levels of FGF10 were repeatedly illustrated in tracheal aspirates and lung explants of BPD patients [ 47 , 114 ], while transgenic mice overexpressing FGF10 seem to preserve the normal lung structure [ 122 ]. In one latest pioneer preclinical study, i.p administration of recombinant FGF10 triggered de novo alveologenesis in newborn mice with pre-existing BPD-like injuries [ 122 ].…”

“…Reduced levels of FGF10 were repeatedly illustrated in tracheal aspirates and lung explants of BPD patients [ 47 , 114 ], while transgenic mice overexpressing FGF10 seem to preserve the normal lung structure [ 122 ]. In one latest pioneer preclinical study, i.p administration of recombinant FGF10 triggered de novo alveologenesis in newborn mice with pre-existing BPD-like injuries [ 122 ]. Despite being a hyperoxia mouse model, it pointed towards the potential of FGF10 as a promising therapeutic approach to be further validated by preclinical IAI models, given that FGF10 is regulated by both infectious and hyperoxia insults [ 78 , 99 , 114 , 122 ].…”

“…In one latest pioneer preclinical study, i.p administration of recombinant FGF10 triggered de novo alveologenesis in newborn mice with pre-existing BPD-like injuries [ 122 ]. Despite being a hyperoxia mouse model, it pointed towards the potential of FGF10 as a promising therapeutic approach to be further validated by preclinical IAI models, given that FGF10 is regulated by both infectious and hyperoxia insults [ 78 , 99 , 114 , 122 ].…”

The Role of Insulin Receptor Substrate Proteins in Bronchopulmonary Dysplasia and Asthma: New Potential Perspectives

“…Hyperoxic injury is one of the main risk factors in BPD pathogenesis, which is thought to disrupt critical signaling pathways that induce lung development, including branching and septation [ 76 ]. Several signaling pathways contributing to these processes have been described, such as IGFR [ 5 ], FGF10 [ 77 , 78 ], and TGF-β [ 79 ] signaling pathways, where the IRS proteins might serve as a common component ( Figure 3 ) [ 80 , 81 ].…”