Fgf10 deficiency is causative for lethality in a mouse model of bronchopulmonary dysplasia

Abstract

Inflammation-induced FGF10 protein deficiency is associated with bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely born infants characterized by arrested alveolar development. So far, experimental evidence for a direct role of FGF10 in lung disease is lacking. Using the hyperoxia-induced neonatal lung injury as a mouse model of BPD, the impact of Fgf10 deficiency in Fgf10+/− versus Fgf10+/+ pups was investigated. In normoxia, no lethality of Fgf10+/+ or Fgf10+/− pups was observed. By contrast, all Fgf10+/− pups died within 8 days of hyperoxic injury, with lethality starting at day 5, whereas Fgf10+/+ pups were all alive. Lungs of pups from the two genotypes were collected on postnatal day 3 following normoxia or hyperoxia exposure for further analysis. In hyperoxia, Fgf10+/− lungs exhibited increased hypoalveolarization. Analysis by FACS of the Fgf10+/− versus control lungs in normoxia, revealed a decreased ratio of alveolar epithelial type II (AECII) cells over total Epcam-positive cells. In addition, gene array analysis indicated reduced AECII and increased AECI transcriptome signatures in isolated AECII cells from Fgf10+/− lungs. Such an imbalance in differentiation is also seen in hyperoxia and associated with reduced mature surfactant protein B and C expression. Attenuation of the activity of Fgfr2b ligands post-natally in the context of hyperoxia lead also to increased lethality with decreased surfactant expression. In summary, decreased Fgf10 mRNA levels leads to congenital lung defects, which are compatible with postnatal survival, but which compromise the ability of the lungs to cope with sub-lethal hyperoxic injury. Fgf10 deficiency affects quantitatively and qualitatively the formation of AECII cells. In addition, Fgfr2b ligands are also important for repair after hyperoxia exposure in neonates. Deficient AECII cells could be an additional complication for patients with BPD.

A critical role for miR-142 in alveolar epithelial lineage formation

“…We also explored the status of Fibroblast growth factor 10 (Fgf10) signaling, a key pathway reported to influence alveolar epithelial lineage formation (Chao et al, 2017; Ramasamy et al, 2007). We found that the expression of Fgf10 was not changed but a very significant increase in the expression of its receptor, Fgfr2b , in KO vs. Control lungs (p= 0.0018) was observed (Fig.…”

“…5D). Recently, we showed that Fgf10 might represent a crucial molecule, controlling the differentiation of the bipotent progenitor cells towards the AT2 lineage (Chao et al, 2017). Using Fgf10 heterozygous ( Fgf10 +/- ) lungs, we demonstrated a decrease in the AT2/AT1 cell ratio.…”

Fibroblast Growth Factor 10 Attenuates Renal Damage by Regulating Endoplasmic Reticulum Stress After Ischemia–Reperfusion Injury

“…Despite the current clinical advances in prevention and treatment, the morbidity and mortality of AKI in hospitalized patients remain very high (Basile et al, 2012;Winterberg and Lu, 2012). As a crucial mesenchymal-epithelial signaling growth factor in embryonic development, tissue repair, and regeneration, the role of FGF10 has been investigated in several disease conditions such as cerebral ischemia injury, pulmonary fibrosis, and wound healing (Li et al, 2016;Chen et al, 2017;Chao et al, 2017;El Agha et al, 2017). However, whether FGF10 is capable of delivering a protective effect on AKI in rat model of I/R injury is still unclear.…”

FGF receptors control alveolar elastogenesis

“…An array of mutants in FGF ligands or receptors exhibit phenotypes at multiple stages of lung development, suggestive of diverse roles of this signaling pathway (Abler et al, 2009;Al Alam et al, 2015;Chao et al, 2017;Hokuto et al, 2003;Usui et al, 2004;Yi et al, 2009;Yin et al, 2011;Yu et al, 2010). The majority of these mutants affect prenatal developmental steps.…”