Sex-specific differences in the severity of pulmonary hypoplasia in experimental congenital diaphragmatic hernia and implications for extracellular vesicle-based therapy
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In brief
In brief
Study examines sex-specific differences in lung underdevelopment caused by congenital diaphragmatic hernia in mice and evaluates amniotic fluid stem cell extracellular vesicles as therapy. Results show male predominance in CDH but no sex differences in disease severity or treatment response, with AFSC-EVs improving lung growth, vascularization, and reducing inflammation regardless of biological sex.
- Male fetuses show higher CDH incidence in this nitrofen model, but pulmonary hypoplasia severity is sex-independent.
- AFSC-EV therapy improves lung growth, vascularization (CD31/eNOS), and reduces inflammation (IL-1β/TNF-α) in CDH lungs.
- Therapeutic response to AFSC-EVs does not differ by fetal sex, suggesting uniform antenatal treatment protocols.
- Ex vivo lung culture with AFSC-EVs demonstrates measurable reversal of CDH-associated pulmonary hypoplasia.
- Extracellular vesicle-based regenerative therapy shows promise for prenatal CDH management regardless of fetal sex.
Written by the GCMD Library team from the article.
Abstract
Purpose
Amniotic fluid stem cell extracellular vesicles (AFSC-EVs) hold regenerative potential to treat hypoplastic lungs secondary to congenital diaphragmatic hernia (CDH). This study aims to investigate sex-specific differences in pulmonary hypoplasia severity and responses to AFSC-EV administration in an experimental CDH mouse model.
Methods
C57BL/6J dams were fed with nitrofen + bisdiamine (left-sided CDH) or olive oil only (control) at embryonic day (E) 8.5. Lungs were dissected (E18.5), grown ex vivo and treated with medium ± AFSC-EVs that were collected via ultracentrifugation and characterized (nanoparticle tracking analysis, electron microscopy, Western blotting). Pulmonary hypoplasia was assessed via mean linear intercept (MLI). Gene and protein expression changes (Cd31, Enos, Il1b, TNFa) were measured via RT-qPCR and immunofluorescence. Pups were genotyped for Sry.
Results
Experimental CDH showed a male predominance without sex differences for pulmonary hypoplasia severity, fetal lung vascularization, and inflammation. AFSC-EV administration led to improved lung growth (decreased MLI), improved fetal lung vascularization (increased Cd31 and Enos), and decreased fetal lung inflammation (Il1b, TNFa). There was no sex-specific response to AFSC-EV administration.
Conclusion
This study shows sex-independent impaired lung growth, vascularization and fetal lung inflammation in a CDH mouse model. Antenatal administration of AFSC-EVs reverses aspects of pulmonary hypoplasia secondary to CDH independent of the biological sex.