Umbilical cord blood-derived exosomes from healthy term pregnancies protect against hyperoxia-induced lung injury in mice.

Bronchopulmonary dysplasia (BPD) is a chronic, devastating disease primarily occurring in premature infants. To date, intervention strategies to prevent or treat BPD are limited. We aimed to determine the effects of umbilical cord blood-derived exosomes (UCB-EXOs) from healthy term pregnancies on hyperoxia-induced lung injury and to identify potential targets for BPD intervention. A mouse model of hyperoxia-induced lung injury was created by exposing neonatal mice to hyperoxia after birth until the 14th day post birth. Age-matched neonatal mice were exposed to normoxia as the control. Hyperoxia-induced lung injury mice were intraperitoneally injected with UCB-EXO or vehicle daily for 3 days, starting on day 4 post birth. Human umbilical vein endothelial cells (HUVECs) were insulted with hyperoxia to establish an in vitro model of BPD to investigate angiogenesis dysfunction. Our results showed that UCB-EXO alleviated lung injuries in hyperoxia-insulted mice by reducing histopathological grade and collagen contents in the lung tissues. UCB-EXO also promoted vascular growth and increased miR-185-5p levels in the lungs of hyperoxia-insulted mice. Additionally, we found that UCB-EXO elevated miR-185-5p levels in HUVECs. MiR-185-5p overexpression inhibited cell apoptosis, whereas promoted cell migration in HUVECs exposed to hyperoxia. The luciferase reporter assay results revealed that miR-185-5p directly targeted cyclin-dependent kinase 6 (CDK6), which was downregulated in the lungs of hyperoxia-insulted mice. Together, these data suggest that UCB-EXO from healthy term pregnancies protect against hyperoxia-induced lung injuries via promoting neonatal pulmonary angiogenesis partially by elevating miR-185-5p.

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

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.

[A clinical analysis of neurobehavioral development within one year after birth in preterm infants with bronchopulmonary dysplasia].

OBJECTIVE: To study the effect of bronchopulmonary dysplasia (BPD) on neurobehavioral development within one year after birth in preterm infants. METHODS: A retrospective analysis was performed for the preterm infants with a gestational age of <34 weeks who were born from September 2017 to December 2019 and completed the follow-up assessments of neurobehavioral development at the corrected gestational ages of 40 weeks and 3, 6, and 12 months. According to their diagnosis, they were divided into a BPD group with 23 infants and a non-BPD group with 27 infants. The outcome of neurobehavioral development was compared between the two groups at different time points. RESULTS: There was no significant difference in the neonatal behavioral neurological assessment score between the BPD and non-BPD groups at the corrected gestational age of 40 weeks (P>0.05). Based on the Gesell Developmental Scale, compared with the non-BPD group, the BPD group had significantly lower global developmental quotient (DQ) and DQs of fine motor, adaptive behavior, and personal-social behavior at the corrected gestational ages of 3, 6, and 12 months (P<0.05). For both groups, the DQ of language at the corrected gestational age of 6 months was significantly higher than that at the corrected gestational age of 12 months (P<0.017), the DQ of personal-social behavior at the corrected gestational age of 6 months was significantly higher than that at the corrected gestational age of 3 months (P<0.017), and the DQ of adaptive behavior at the corrected gestational age of 12 months was significantly higher than that at the corrected gestational ages of 3 and 6 months (P<0.017). Based on the BSID-II scale, there were no significant differences in mental development index and psychomotor development index at each time point between the two groups (P>0.05). The mental development index at the corrected gestational age of 3 months was significantly higher than that at the corrected gestational ages of 6 and 12 months in both groups (P<0.001). CONCLUSIONS: Preterm infants with BPD have delayed neurodevelopment within one year after birth compared with those without BPD, which should be taken seriously in clinical practice.