Loukogeorgakis, Stavros P;
Michielin, Federica;
Al-Juffali, Noura;
Jimenez, Julio;
Shibuya, Soichi;
Allen-Hyttinen, Jessica;
Eastwood, Mary Patrice;
... De Coppi, Paolo; + view all
(2025)
Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-associated Pulmonary Abnormalities.
American Journal of Respiratory and Critical Care Medicine
10.1164/rccm.202401-0161OC.
(In press).
Preview |
Text
loukogeorgakis-et-al-2025-prenatal-vegf-nano-delivery-reverses-congenital-diaphragmatic-hernia-associated-pulmonary.pdf - Accepted Version Download (23MB) | Preview |
Abstract
RATIONALE: Congenital diaphragmatic hernia (CDH) results in lung hypoplasia. In severe cases, tracheal occlusion (TO) can be offered to promote lung growth. However the benefit is limited, and novel treatments are required to supplement TO. Vascular endothelial growth factor (VEGF) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known. OBJECTIVES: To investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology. METHODS: Fetal lungs from CDH patients were used to determine pulmonary morphology and VEGF expression. A novel human ex vivo model of fetal lung compression recapitulating CDH features was developed and used to determine the effect of exogenous VEGF supplementation. A nanoparticle-based approach for intra-pulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds (ND-VEGF) and was tested in experimental CDH in vivo. MEASUREMENTS AND MAIN RESULTS: VEGF expression was downregulated in distal pulmonary epithelium of human CDH fetuses in conjunction with attenuated cell proliferation. The compression model resulted in impaired branching morphogenesis similar to CDH and downregulation of VEGF expression in conjunction with reduced proliferation of terminal bud epithelial progenitors; these could be reversed by exogenous supplementation of VEGF. Prenatal delivery of VEGF with the ND-VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodelling that was complementary to that achieved by TO alone with appearances comparable to healthy controls. CONCLUSIONS: This innovative approach could have a significant impact on the treatment of CDH.
| Type: | Article |
|---|---|
| Title: | Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-associated Pulmonary Abnormalities |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1164/rccm.202401-0161OC |
| Publisher version: | https://doi.org/10.1164/rccm.202401-0161oc |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. - For the purpose of open access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. |
| Keywords: | Alveolar Epithelium, Congenital Diaphragmatic Hernia, Mechanical Compression, Nanoparticles, VEGF |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10205062 |
Loading...
Loading...Loading...Loading...Archive Staff Only
 |
View Item |
