Antenatal Administration of Extracellular Vesicles Derived From Amniotic Fluid Stem Cells Improves Lung Function in Neonatal Rats With Congenital Diaphragmatic Hernia

• Published in: Journal of pediatric surgery 2024-09, Vol.59 (9), p.1771-1777
• Main Authors: Figueira, Rebeca L., Khoshgoo, Naghmeh, Doktor, Fabian, Khalaj, Kasra, Islam, Tasneem, Moheimani, Nazgol, Blundell, Matisse, Antounians, Lina, Post, Martin, Zani, Augusto
• Format: Article
• Language: English
• Subjects: Exosomes; Lung development; Pulmonary hypertension; Regenerative medicine; Respiratory distress syndrome
• ISSN: 0022-3468; 1531-5037; 1531-5037
• DOI: 10.1016/j.jpedsurg.2024.02.029

The severity of pulmonary hypoplasia is a main determinant of outcome for babies with congenital diaphragmatic hernia (CDH). Antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) has been shown to rescue morphological features of lung development in the rat nitrofen model of CDH. Herein, we evaluated whether AFSC-EV administration to fetal rats with CDH is associated with neonatal improvement in lung function. AFSC-EVs were isolated by ultracentrifugation and characterized by size, morphology, and canonical marker expression. At embryonic (E) day 9.5, dams were gavaged with olive oil (control) or nitrofen to induce CDH. At E18.5, fetuses received an intra-amniotic injection of either saline or AFSC-EVs. At E21.5, rats were delivered and subjected to a tracheostomy for mechanical ventilation (flexiVent system). Groups were compared for lung compliance, resistance, Newtonian resistance, tissue damping and elastance. Lungs were evaluated for branching morphogenesis and collagen quantification. Compared to healthy control, saline-treated pups with CDH had fewer airspaces, more collagen deposition, and functionally exhibited reduced compliance and increased airway resistance, elastance, and tissue damping. Conversely, AFSC-EV administration resulted in improvement of lung mechanics (compliance, resistance, tissue damping, elastance) as well as lung branching morphogenesis and collagen deposition. Our studies show that the rat nitrofen model reproduces lung function impairment similar to that of human babies with CDH. Antenatal administration of AFSC-EVs improves lung morphology and function in neonatal rats with CDH. N/A (animal and laboratory study). What is currently known about this topic?•Pulmonary hypoplasia is a primary determinant for the impaired lung function in infants with CDH.•Impaired airway branching and abnormal lung collagen deposition directly affect lung mechanics, such as compliance and resistance.•Antenatal administration of AFSC-EVs rescues features of lung development in human and rodent models of pulmonary hypoplasia. What new information is contained in this article?•Ventilation studies in neonatal rats with CDH reveal that the nitrofen model reproduces lung function impairment like that of human babies with CDH.•Intra-amniotic administration of AFSC-EVs in fetal rats with CDH improves not only postnatal lung branching morphogenesis and collagen levels, but also pulmonary function parameters