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Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-Associated Pulmonary Abnormalities

ABSTRACT: Congenital diaphragmatic hernia (CDH) affects 1-2 in 5,000 neonates who are born with hypoplastic lungs leading to significant morbidity and mortality. In severe cases tracheal occlusion (TO) can be offered to promote lung growth through airway stretch, but such growth remains limited. Vascular endothelial growth factor (VEGF), a key mediator of normal lung development, is downregulated in animal models of CDH, but its role in CDH-associated lung pathology in humans is not known. Using 18-22 post-conception week fetal lungs from CDH patients, we demonstrated for the first time that lung hypoplasia in this setting is associated with impaired VEGF expression and reduced pulmonary epithelial cell proliferation. We then developed a human ex vivo model of fetal lung compression relevant to CDH, in which a mechanical constraint was added to cultured lung fragments. Our model recapitulated impaired branching morphogenesis observed in CDH fetal lungs, and scRNAseq revealed significant reduction of the proliferative potential of terminal bud epithelial progenitors with concomitant reduction in expression of VEGF. Importantly, the exogenous supplementation of recombinant VEGF in this setting induced a significant increase of terminal bud progenitor cell proliferation, comparable to non-compressed control tissue. Finally, we developed a novel therapeutic agent delivery platform by conjugating recombinant VEGF on the surface of nanoparticles (nanodiamonds; ND-VEGF). In utero, intratracheal administration of ND-VEGF into the in vivo TO Nitrofen rat model of CDH resulted in lung growth as well as pulmonary arterial remodelling leading to histological appearances comparable to healthy controls. The beneficial effects of ND-VEGF were abrogated by co-administration of a selective VEGF-receptor-2 (KDR/Flk1) inhibitor and were not observed when unconjugated VEGF was delivered. This innovative approach could have a significant impact on the treatment of CDH.

ORGANISM(S): Mus musculus

PROVIDER: GSE267778 | GEO | 2025/05/17

REPOSITORIES: GEO

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Project description:Underdeveloped lungs are the primary cause of death in premature infants, however, little is known about stem and progenitor cell maintenance during human lung development. In this study, we have identified that FGF7, Retinoic Acid and CHIR-99021, a small molecule that inhibits GSK3 to activate Wnt signaling, support in vitro maintenance of primary human fetal lung bud tip progenitor cells in a progenitor state. Furthermore, these factors are sufficient to derive a population of human bud tip-like progenitor cells in 3D organoid structures from human pluripotent stem cells (hPSC). Functional studies showed that hPSC-derived bud tip progenitor organoids do not contain any mesenchymal cell types, maintain multilineage potential in vitro and are able to engraft into the airways of injured mice and respond to systemic factors. We performed RNA-sequencing to assess the degree of similarity in global gene expression profiles between the full human fetal lung (59-127 days gestation), isolated human fetal bud tip progenitors, organoids grown from primary fetal bud tip progenitors, and hPSC-derived bud tip organoids. Results showed that hPSC-derived organoids have molecular profiles similar to organoids generated from primary human fetal lung tissue. Gene expression differences between hPSC-derived bud tip organoids and fetal progenitor organoids may be related to the presence of contaminating mesenchymal cells in primary cultures. hPSC-derived bud tip organoids are generated from a well-defined human cell sources, offering a distinct advantage over rare primary tissue as a means to study human specific lung development, homeostasis and disease. Sample Nomenclature - Description ------------------------------------------------------------------------- Peripheral fetal lung the distal/peripheral portion of the fetal lung (i.e., distal 0.5 cm) was excised from the rest of the lung using a scalpel. This includes all components of the lung (e.g., epithelial, mesenchymal, vascular). Isolated fetal bud tip the bud peripheral portion of the fetal lung was excised with a scalpel and subjected to enzymatic digestion and microdissection. The epithelium was dissected and separated from the mesenchyme, but a small amount of associated mesenchyme likely remained. Fetal progenitor organoid 3D organoid structures that arose from culturing isolated fetal epithelial bud tips. Foregut spheroid 3D foregut endoderm structure as described in Dye et al. (2015). Gives rise to patterned lung organoid (PLO) when grown in 3F medium. Patterned lung organoid (PLO) lung organoids that were generated by differentiating hPSCs, as described throughout the manuscript. Bud tip organoid organoids derived from PLOs, enriched for SOX2/SOX9 co-expressing cells, and grown/passaged in 3F medium.

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Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-Associated Pulmonary Abnormalities

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