Fetal hypoplastic lungs have multilineage inflammation that is reversed by amniotic fluid stem cell extracellular vesicle treatment

Antenatal administration of extracellular vesicles from amniotic fluid stem cells (AFSC-EVs) reverses features of pulmonary hypoplasia in models of congenital diaphragmatic hernia (CDH). However, it remains unknown which lung cellular compartments and biological pathways are affected by AFSC-EV ther...

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Published in:Science advances 2024-07, Vol.10 (30), p.eadn5405
Main Authors: Antounians, Lina, Figueira, Rebeca Lopes, Kukreja, Bharti, Litvack, Michael L, Zani-Ruttenstock, Elke, Khalaj, Kasra, Montalva, Louise, Doktor, Fabian, Obed, Mikal, Blundell, Matisse, Wu, Taiyi, Chan, Cadia, Wagner, Richard, Lacher, Martin, Wilson, Michael D, Post, Martin, Kalish, Brian T, Zani, Augusto
Format: Article
Language:English
Subjects:
Amniotic Fluid - cytology
Amniotic Fluid - metabolism
Animals
Cell Differentiation
Disease Models, Animal
Extracellular Vesicles - metabolism
Female
Fetus
Hernias, Diaphragmatic, Congenital - metabolism
Hernias, Diaphragmatic, Congenital - pathology
Hernias, Diaphragmatic, Congenital - therapy
Humans
Inflammation - metabolism
Inflammation - pathology
Lung - metabolism
Lung - pathology
Macrophages - metabolism
Pregnancy
Rats
Stem Cell Transplantation - methods
Stem Cells - metabolism
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Summary:Antenatal administration of extracellular vesicles from amniotic fluid stem cells (AFSC-EVs) reverses features of pulmonary hypoplasia in models of congenital diaphragmatic hernia (CDH). However, it remains unknown which lung cellular compartments and biological pathways are affected by AFSC-EV therapy. Herein, we conducted single-nucleus RNA sequencing (snRNA-seq) on rat fetal CDH lungs treated with vehicle or AFSC-EVs. We identified that intra-amniotically injected AFSC-EVs reach the fetal lung in rats with CDH, where they promote lung branching morphogenesis and epithelial cell differentiation. Moreover, snRNA-seq revealed that rat fetal CDH lungs have a multilineage inflammatory signature with macrophage enrichment, which is reversed by AFSC-EV treatment. Macrophage enrichment in CDH fetal rat lungs was confirmed by immunofluorescence, flow cytometry, and inhibition studies with GW2580. Moreover, we validated macrophage enrichment in human fetal CDH lung autopsy samples. Together, this study advances knowledge on the pathogenesis of pulmonary hypoplasia and further evidence on the value of an EV-based therapy for CDH fetuses.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adn5405