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Gestational Diabetes Mellitus Impedes Fetal Lung Development Through Exosome-Dependent Crosstalk Between Trophoblasts
Pengzheng Chen1, Mengqi Gu1, Shuting Wan1
1Department of Obstetrics and Gynaecology, Shandong Provincial Hospital, Shandong University, Jinan, People's Republic of China.
Insights
Gestational diabetes mellitus (GDM) alters trophoblast-derived exosomes, impairing fetal lung development (FLUD) by disrupting cell function and increasing apoptosis. This study reveals exosome dysregulation as a key mechanism in GDM-induced FLUD.
Area of Science:
- Reproductive biology
- Developmental biology
- Cellular and molecular medicine
Background:
- Fetal lung underdevelopment (FLUD) is linked to severe neonatal respiratory issues.
- Gestational diabetes mellitus (GDM) is a significant risk factor for FLUD, but the underlying mechanisms involving trophoblasts are not fully understood.
Purpose of the Study:
- To investigate the role of trophoblast-derived exosomes in GDM-induced FLUD.
- To elucidate the impact of altered exosome content from GDM pregnancies on fetal lung development.
Main Methods:
- Established in vitro, ex vivo, and in vivo models using normal and GDM trophoblast-derived exosomes.
- Analyzed exosome concentration, miRNA content, and effects on A549 alveolar cells and fetal lung explants.
- Assessed fetal lung development in vivo in a GDM model.
Main Results:
- GDM-derived exosomes showed increased concentration and altered miRNA profiles compared to normal exosomes.
- These exosomes suppressed proliferation, impaired biological functions, and increased apoptosis in lung cells.
- Ex vivo and in vivo studies demonstrated significant suppression of fetal lung growth and altered expression of key developmental genes and surfactant proteins.
Conclusions:
- GDM adversely affects trophoblasts, leading to altered exosome content and subsequent FLUD.
- Disrupted crosstalk between trophoblasts and fetal lung epithelial cells via exosomes is a primary mechanism.
- Findings provide insights into the pathogenesis of FLUD in the context of GDM.
Background:
Fetal lung underdevelopment (FLUD) is associated with neonatal and childhood severe respiratory diseases, among which gestational diabetes mellitus (GDM) play crucial roles as revealed by recent prevalence studies, yet mechanism underlying GDM-induced FLUD, especially the role of trophoblasts, is not all known.
Methods:
From the perspective of trophoblast-derived exosomes, we established in vitro, ex vivo, in vivo and GDM trophoblast models. Utilizing placenta-derived exosomes (NUB-exos and GDMUB-exos) isolated from normal and GDM umbilical cord blood plasma and trophoblast-derived exosomes (NC-exos and HG-exos) isolated from HTR8/SVneo trophoblasts medium with/without high glucose treatment, we examined their effects on fetal lung development and biological functions.
Results:
We found that, compared with the NUB-exos group, the exosome concentration increased in GDMUB-exos group, and the content of exosomes also changed evidenced by 61 dysregulated miRNAs. After applying these exosomes to A549 alveolar type II epithelial cells, the proliferation and biological functions were suppressed while the proportion of apoptotic cells was increased as compared to the control. In ex vivo studies, we found that GDMUB-exos showed significant suppression on the growth of the fetal lung explants, where the number of terminal buds and the area of explant surface decreased and shrank. Besides, the expression of Fgf10, Vegfa, Flt-1, Kdr and surfactant proteins A, B, C, and D was downregulated in GDMUB-exos group, whilst Sox9 was upregulated. For in vivo studies, we found significant suppression of fetal lung development in GDMUB-exos group. Importantly, we found consistent alterations when we used NC-exos and HG-exos, suggesting a dominant role of trophoblasts in placenta-derived exosome-induced FLUD.
Conclusion:
In conclusion, GDM can adversely affect trophoblasts and alter exosome contents, causing crosstalk disorder between trophoblasts and fetal lung epithelial cells and finally leading to FLUD. Findings of this study will shine insight into the theoretical explanation for the pathogenesis of FLUD.
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