Extracellular vesicle miRNA-21 is a potential biomarker for predicting chronic lung disease in premature infants

Abstract

Premature infants are often exposed to positive pressure ventilation and supplemental oxygen, which leads to the development of chronic lung disease (CLD). There are currently no standard serum biomarkers used for prediction or early detection of patients who go on to develop CLD. MicroRNAs (miRNAs) are a novel class of naturally occurring, short, noncoding substances that regulate gene expression at the posttranscriptional level and cause translational inhibition and/or mRNA degradation and present in body fluids packaged in extracellular vesicles (EVs), rendering them remarkably stable. Our aim was to evaluate miRNAs identified in serum EVs of premature infants as potential biomarkers for CLD. Serum EVs were extracted from premature infants at birth and on the 28th day of life (DOL). Using a human miRNA array, we identified 62 miRNAs that were universally expressed in CLD patients and non-CLD patients. Of the 62 miRNAs, 59 miRNAs and 44 miRNAs were differentially expressed on DOL0 and DOL28 in CLD and non-CLD patients, respectively. Of these miRNAs, serum EV miR-21 was upregulated in CLD patients on DOL28 compared with levels at birth and downregulated in non-CLD patients on DOL28 compared with levels at birth. In neonatal mice exposed to hyperoxia for 7days, as a model of CLD, five miRNAs (miR-34a, miR-21, miR-712, miR-682, and miR-221) were upregulated, and 7 miRNAs (miR-542–5p, miR-449a, miR-322, miR-190b, miR-153, miR-335–3p, miR-377) were downregulated. MiR-21 was detected as a common miRNA that changed in CLD patients and in the hyperoxia exposed mice. We conclude that EV miR-21 may be a biomarker of CLD.

Sorting Mechanisms for MicroRNAs into Extracellular Vesicles and Their Associated Diseases

“…Hyperoxia-treated lung epithelial cells caused an upregulation of miR-320a and miR-221 in MVs [45]. In another recent in vivo experiment by Go and colleagues, 2020, hyperoxia-treated mice developed increased levels of miR-21 in serum EVs [46]. These authors furthered their findings by measuring EV miRNA in serum derived from premature human infants as a model of chronic lung disease (CLD).…”

“…These authors furthered their findings by measuring EV miRNA in serum derived from premature human infants as a model of chronic lung disease (CLD). Predictably based on the mouse experiments, they identified elevated serum EV levels of miR-21 in human infants [46]. These findings suggest that miR-21 is likely involved in the lung injury process associated with CLD.…”

“…MicroRNA-21 has been previously shown to target and suppress the tumor suppressor protein Programmed Cell Death 4 (PDCD4) [47]. Go and colleagues, 2020, also identified that miR-21 suppressed PDCD4, and thus, suggested that the elevated serum EV miR-21 could be a potential biomarker of CLD [46].…”

“…Chronic Lung Disease Hyperoxia-treated lung epithelial cells caused an upregulation of miR-320a and miR-221 in MVs [45] CLD causes elevated serum EV levels of miR-21 in human infants [46] Immune Response IL-4 causes upregulated miR-138-5p and miR-149-5p in BMDM-derived exosomes [48] Neuroinflammation Astrocytes stimulated with IL-1β increased exosomal levels of let-7d, miR-126, miR-130b, miR-139-5p, and miR-141-3p [50] Exosomal miR-193-3p delivered to a SAH mouse caused a reduction in HDAC3 reduced inflammation [52] Table 2. Cont.…”

Tracheal Aspirate miRNA Signatures in Preterm Infants with Severe Bronchopulmonary Dysplasia

“…The potential of TA miRNAs to predict disease severity in neonatal and pediatric lung disease is promising and warrants additional investigation. This is highlighted by the fact that TAs are obtained relatively easy from endotracheal tube suctioning in infants receiving invasive mechanical ventilation [17,18]. Moreover, TAs are a vital source of information to study molecular pathways related to the microenvironment of the developing lung and could not only provide a source of novel biomarkers for BPD diagnosis, but also identify molecular events occurring during lung development in the context of the disease [17,19,20].…”