Fetal Tracheal Occlusion Increases Lung Basal Cells via Increased Yap Signaling

Abstract

Fetal endoscopic tracheal occlusion (FETO) is an emerging surgical therapy for congenital diaphragmatic hernia (CDH). Ovine and rabbit data suggested altered lung epithelial cell populations after tracheal occlusion (TO) with transcriptomic signatures implicating basal cells. To test this hypothesis, we deconvolved mRNA sequencing (mRNA-seq) data and used quantitative image analysis in fetal rabbit lung TO, which had increased basal cells and reduced ciliated cells after TO. In a fetal mouse TO model, flow cytometry showed increased basal cells, and immunohistochemistry demonstrated basal cell extension to subpleural airways. Nuclear Yap, a known regulator of basal cell fate, was increased in TO lung, and Yap ablation on the lung epithelium abrogated TO-mediated basal cell expansion. mRNA-seq of TO lung showed increased activity of downstream Yap genes. Human lung specimens with congenital and fetal tracheal occlusion had clusters of subpleural basal cells that were not present in the control. TO increases lung epithelial cell nuclear Yap, leading to basal cell expansion.

A tracheal aspirate-derived airway basal cell model reveals a proinflammatory epithelial defect in congenital diaphragmatic hernia

“…Novel therapeutics, such as amniotic fluid derived extracellular vesicles can promote prenatal lung maturation in CDH animal models (59, 60). Future studies could explore how such therapeutics can rescue CDH phenotypes in our in vitro model and large animal models before clinical testing in CDH patients when applied alone or in combination with FETO (61). Lastly, TA BSCs derived from larger CDH patient cohorts, in combination with genetic mapping of patient-specific de novo mutations, is warranted to deepen our understanding of the pathogenesis of lung defects in CDH.…”

Fetal lung vascular development is disrupted by mechanical compression and rescued by administration of amniotic fluid stem cell extracellular vesicles via regulation of the Hippo signaling pathway

“…This signaling pathway is a conserved mechanosensitive pathway that regulates cell proliferation through response to mechanical stimuli and is critical for organ development [34][35][36][37][38][39][40] . The Hippo signaling pathway has been reported to be dysregulated in rodent models of CDH 39,[41][42][43] . Serapiglia et al reported that fetal mouse with conditional depletion of Yap from the lung epithelium had reduced lung basal cell population in comparison to fetal lungs from wild-type mouse 42 .…”

“…The Hippo signaling pathway has been reported to be dysregulated in rodent models of CDH 39,[41][42][43] . Serapiglia et al reported that fetal mouse with conditional depletion of Yap from the lung epithelium had reduced lung basal cell population in comparison to fetal lungs from wild-type mouse 42 . Kahnamoui et al demonstrated that the Hippo signaling effector protein Yap is inactive in nitrofen-induced hypoplastic lungs in comparison to control lungs 43 .…”