International Journal of Nanomedicine (Feb 2023)
Gestational Diabetes Mellitus Impedes Fetal Lung Development Through Exosome-Dependent Crosstalk Between Trophoblasts and Lung Epithelial Cells
Abstract
Pengzheng Chen,1 Mengqi Gu,1 Shuting Wan,1 Xiaotong Jiang,1 Fengyuan Zhang,2 Yuchen Li,2 Qian Zhou,2 Yuan Lu,2 Lei Li,1– 3 Xietong Wang1– 4 1Department of Obstetrics and Gynaecology, Shandong Provincial Hospital, Shandong University, Jinan, People’s Republic of China; 2Department of Obstetrics and Gynaecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 3Laboratory of Medical Science and Technology Innovation Center (Institute of Translational Medicine), Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, People’s Republic of China; 4Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital, Jinan, People’s Republic of ChinaCorrespondence: Lei Li; Xietong Wang, Department of Obstetrics and Gynaecology, Shandong Provincial Hospital, Shandong University, Jinan, People’s Republic of China, Tel +8615168889200 ; +8615168888928, Email [email protected]; [email protected]: 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.Keywords: gestational diabetes mellitus, fetal lung underdevelopment, trophoblast, placenta-derived exosome, trophoblast-derived exosomes
