Umbilical Cord Blood-Derived Exosomes From Very Preterm Infants With Bronchopulmonary Dysplasia Impaired Endothelial Angiogenesis: Roles of Exosomal MicroRNAs

Abstract

Premature infants have a high risk of bronchopulmonary dysplasia (BPD), which is characterized by abnormal development of alveoli and pulmonary vessels. Exosomes and exosomal miRNAs (EXO-miRNAs) from bronchoalveolar lavage fluid are involved in the development of BPD and might serve as predictive biomarkers for BPD. However, the roles of exosomes and EXO-miRNAs from umbilical cord blood of BPD infants in regulating angiogenesis are yet to be elucidated. In this study, we showed that umbilical cord blood-derived exosomes from BPD infants impaired angiogenesis in vitro. Next-generation sequencing of EXO-miRNAs from preterm infants without (NBPD group) or with BPD (BPD group) uncovered a total of 418 differentially expressed (DE) EXO-miRNAs. These DE EXO-miRNAs were primarily enriched in cellular function-associated pathways including the PI3K/Akt and angiogenesis-related signaling pathways. Among those EXO-miRNAs which are associated with PI3K/Akt and angiogenesis-related signaling pathways, BPD reduced the expression of hsa-miR-103a-3p and hsa-miR-185-5p exhibiting the most significant reduction (14.3% and 23.1% of NBPD group, respectively); BPD increased hsa-miR-200a-3p expression by 2.64 folds of the NBPD group. Furthermore, overexpression of hsa-miR-103a-3p and hsa-miR-185-5p in normal human umbilical vein endothelial cells (HUVECs) significantly enhanced endothelial cell proliferation, tube formation, and cell migration, whereas overexpressing hsa-miR-200a-3p inhibited these cellular responses. This study demonstrates that exosomes derived from umbilical cord blood of BPD infants impair angiogenesis, possibly via DE EXO-miRNAs, which might contribute to the development of BPD.

Intrauterine Hypoxia and Epigenetic Programming in Lung Development and Disease

“…These two miRNAs were involved in the pulmonary vasculature and pulmonary hypertension and intrauterine growth restriction [116,117], which are closely associated with BPD. A more recent study found that umbilical cord blood-derived exosomal miRNAs from very preterm human infants with BPD were 90 downregulated (e.g., miR-103a-3p and miR-185-5p) and 328 upregulated (e.g., miR-200a-3p), which were associated with PI3K/Akt and angiogenesis-related signaling pathways [98]. Further, overexpression of miR-103a-3p and miR-185-5p augmented endothelial cell proliferation, migration and tube formation, while overexpression of miR-200a-3p impeded these angiogenic responses [98].…”

“…A more recent study found that umbilical cord blood-derived exosomal miRNAs from very preterm human infants with BPD were 90 downregulated (e.g., miR-103a-3p and miR-185-5p) and 328 upregulated (e.g., miR-200a-3p), which were associated with PI3K/Akt and angiogenesis-related signaling pathways [98]. Further, overexpression of miR-103a-3p and miR-185-5p augmented endothelial cell proliferation, migration and tube formation, while overexpression of miR-200a-3p impeded these angiogenic responses [98]. Additionally, miR-34a expression was found to be decreased in the postnatal hypoxia-induced mouse model of BPD/lung injury [101].…”

CircRNA, lncRNA, and mRNA profiles of umbilical cord blood exosomes from preterm newborns showing bronchopulmonary dysplasia

“…Among them, hsa_circ_0086913/hsa-miR-103a-3p/transmembrane 4 L six family member 1 (TM4SF1) was predicted with a PCC of 0.93. In a recent study, the researchers found that the expression level of hsa-miR-103a-3p related to the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway was decreased in UCB-derived exosomes from the BPD group compared with the NBPD group [ 16 ]. Further, the overexpression of hsa-miR-103a-3p in normal HUVECs significantly promoted cell proliferation, cell migration, and tube formation [ 16 ].…”

“…Many researchers reported that exosomes played a crucial role in BPD [11][12][13], and may function through selected proteins, lipids, nucleic acids, and glycoconjugates [14,15]. In addition, a recent study demonstrated that UCB-derived exosomes of infants with BPD impair angiogenesis, potentially through differentially expressed exosomal miRNAs [16]. However, the roles of UCB-derived exosomal circular RNAs (cir-cRNAs) of infants with BPD remain poorly understood.…”

The implications of exosomes in pregnancy: emerging as new diagnostic markers and therapeutics targets

“…It has been shown that exosomes' ability to modulate endothelial cell migration decreased over time [ 82 ]. Exosomes could originate from maternal circulation and cord blood and promote endothelial cell proliferation, migration, and tube formation [ 83 ]. The activity of maternal serum-derived exosomes is higher than that of exosomes from cord blood [ 84 ].…”