Prenatal VEGF Nanodelivery Reverses Congenital Diaphragmatic Hernia–associated Pulmonary Abnormalities

<b>Rationale:</b> 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. VEGF (vascular endothelial growth factor) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known. <b>Objectives:</b> To investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology. <b>Methods:</b> Fetal lungs from patients with CDH were used to determine pulmonary morphology and VEGF expression. A novel human <i>ex vivo</i> 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 intrapulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds, which was tested in experimental CDH <i>in vivo</i>. <b>Measurements and Main Results:</b> VEGF expression was downregulated in the 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 functionalized nanodiamond VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodeling that was complementary to that achieved by TO alone with appearances comparable to healthy controls. <b>Conclusions:</b> This innovative approach could have a significant impact on the treatment of CDH.

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Publication Details

Journal
American Journal of Respiratory and Critical Care Medicine
Published
2025-02-18
DOI
https://doi.org/10.1164/rccm.202401-0161oc
Citations
7
Primary Topic
Congenital Diaphragmatic Hernia Studies
Type
article
Field-Weighted Citation Impact
14.04

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article

Prenatal VEGF Nanodelivery Reverses Congenital Diaphragmatic Hernia–associated Pulmonary Abnormalities

Nikhil Sindhwani, Theodoros Xenakis, Noura Al‐Juffali, Jessica Allen-Hyttinen et al.
7 citations
American Journal of Respiratory and Critical Care Medicine
Congenital Diaphragmatic Hernia Studies
14.04
article

Prenatal VEGF Nanodelivery Reverses Congenital Diaphragmatic Hernia–associated Pulmonary Abnormalities

Nikhil Sindhwani, Theodoros Xenakis, Noura Al‐Juffali, Jessica Allen-Hyttinen, Federica Michielin, Paolo De Coppi, Dominic Scaglioni, Nicola Elvassore, Eleonora Naldi, Ahmed S. N. Alhendi, Marko Nikolić, Neil J. Sebire, Camilla Luni, Soichi Shibuya, Peter Carmeliet, Panagiotis Maghsoudlou, Manuela Platé, Julio Jiménez, Simon Eaton, Stavros Loukogeorgakis, Sam M. Janes, Joseph Davidson, Monica Giomo, Camila Girardi Fachin, Francesca Maria Russo, Jan A. Deprest, Mary Patrice Eastwood, Jaan Toelen, Piero G. Pavan, Andre Dos Santos Dias, S Khalaf, Alfonso Tedeschi
article en
7 citations

Abstract

<b>Rationale:</b> 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. VEGF (vascular endothelial growth factor) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known. <b>Objectives:</b> To investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology. <b>Methods:</b> Fetal lungs from patients with CDH were used to determine pulmonary morphology and VEGF expression. A novel human <i>ex vivo</i> 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 intrapulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds, which was tested in experimental CDH <i>in vivo</i>. <b>Measurements and Main Results:</b> VEGF expression was downregulated in the 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 functionalized nanodiamond VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodeling that was complementary to that achieved by TO alone with appearances comparable to healthy controls. <b>Conclusions:</b> This innovative approach could have a significant impact on the treatment of CDH.

American Journal of Respiratory and Critical Care MedicineVol. 211(6)
University of London (GB), Children's Hospital of Philadelphia (US), Universidad del Desarrollo (CL), University of Padua (IT), Great Ormond Street Hospital (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), University College Lahore (PK), Clínica Alemana (CL), Institute for Stem Cell Biology and Regenerative Medicine (IN), VIB-KU Leuven Center for Cancer Biology (BE), Regenerative Medicine Institute (MX), Centre for Inflammation Research (GB), Health and Human Development (2HD) Research Network (CM), Città della Speranza Foundation (IT), University College London (GB), Universidade Federal do Paraná (BR), Universidade Federal de São Paulo (BR), University of Bologna (IT), KU Leuven (BE)
Medical Research Council
Openalex Percentile: Top 1%
Congenital Diaphragmatic Hernia Studies
14.04
DOIOpen Access PDFOpenAlex
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