MicroRNA Let-7b-5p is a Biomarker and Potential Therapeutic Target in Bronchopulmonary Dysplasia

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Abstract RATIONALE: In STOP BPD (Signature of Top Omic Profiles of BPD; R01HL129907) project, we identified clinical and “omic” biomarkers associated with risk of BPD in a prospective cohort of 302 extremely preterm infants. The “omic” biomarkers included transcriptomic (mRNA and miRNA; blood), genomic (whole exome sequencing), proteomic (plasma and urine), and airway microbiomic biomarkers in the first 3 days after birth. The strongest biomarker signal we discovered by small RNA-seq and validated by qPCR was the microRNA let-7b-5p (let-7), with a 46-fold increase (p< 0.001) at birth in the blood of infants who subsequently developed severe BPD (versus no BPD) many weeks later at 36w post-menstrual age (Figure 1A). We also found a 14-fold increase of let-7 on postnatal day 1 in the tracheal aspirate of infants who subsequently developed BPD (Figure 1B), and a 2-fold increase in BPD lung tissue (versus normal preterm lung) (Figure 1C). Our objectives were to: (1) Determine in a new prospective cohort (Let-7b in BPD; R01HL156275) if plasma let-7 concentrations track with lung disease progression, (2) Identify which cell types were the source of let-7, and define effects of hyperoxia exposure on let-7 release, (3) Identify potential mechanisms by which excessive let-7 contributes to BPD, (4) test the hypothesis that let-7 inhibition improves lung development in a newborn mouse model of BPD. METHODS:(1) Compare let-7 in plasma at multiple time points in infants who later develop severe BPD versus those with mild/no BPD; (2) evaluate let-7 expression and release from lung epithelial cells, fibroblasts, and endothelial cells; (3) evaluate effects of let-7 on angiogenesis as HMGA2 is a major target; (4) test if let-7 inhibition during hyperoxia improves alveolar development in newborn mice. RESULTS:(1) Analysis of the first 41 infants in the new cohort (19 with severe BPD; 22 with mild/no BPD) demonstrated increasing separation of plasma let-7 concentrations, with higher let-7 in infants with severe BPD over time (Figure 2); (2) airway epithelial cells were the primary source of let-7, which markedly increased release of let-7 in exosomes with hyperoxia exposure; (3) excessive let-7 inhibited angiogenesis in matrigel assay; (4) let-7 inhibition during hyperoxia exposure improves alveolar development in newborn mice (Figure 3). CONCLUSION: MicroRNA let-7b-5p is not only a early sensitive biomarker for later BPD in extremely preterm infants, but is a mediator of abnormal lung microvascular development, and its inhibition may be a potential therapeutic target for BPD.

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