In utero delivery of miRNA induces epigenetic alterations and corrects pulmonary pathology in congenital diaphragmatic hernia

Abstract

Structural fetal diseases, such as congenital diaphragmatic hernia (CDH) can be diagnosed prenatally. Neonates with CDH are healthy in utero as gas exchange is managed by the placenta, but impaired lung function results in critical illness from the time a baby takes its first breath. During fetal development, lungs are capable of remarkable growth and the fetus does not yet require lung function for gas exchange. MicroRNA (miR) 200b and its downstream targets in the TGF beta pathway are critically involved lung branching morphogenesis. Here we characterize the expression of miR200b and the TGF beta pathway at different gestational times using a rat model of CDH. Fetal rats with CDH are deficient in miR200b at gestational day 18. We demonstrate that NPs loaded with miR200b given systemically to fetal rats result in changes in the TGF beta pathway; these epigenetic changes improve lung size, lung morphology, and lung vascularization. This is the first demonstration of in utero epigenetic therapy to improve lung growth and development in a pre-clinical model. With refinement, this technique could be applied to fetal cases of CDH or other forms of impaired lung development in a minimally invasive fashion.

TGF‐β/Smads signaling pathway, Hippo‐YAP/TAZ signaling pathway, and VEGF: Their mechanisms and roles in vascular remodeling related diseases

“…Through in vitro studies, they found that treatment of miR200b can induce TGF‐β signaling pathways and increase the occurrence of branching morphologies. In their study, they delivered miR200b in utero using PACE NPs to treat a rat model of CDH, and they found that in utero delivery of miR200b induces alterations in the TGF‐β pathway, leads to pulmonary vascular remodeling, and improves PH 45 . Similarly, a recent experiment by Da et al on the treatment of abdominal aortic aneurysms (TAA) in mice found that the application of AGGF could inhibit vascular inflammation and remodeling of TAA by blocking the cleavage of LAP‐TGF‐β1 to form mature TGF‐β1 and inhibiting Smad2/3 and ERK1/2 phosphorylation in VSMCs 46 .…”

“…Congenital diaphragmatic hernia (CDH) is a pulmonary dysplasia characterized by reduced distal airway branches, reduced alveolar numbers, and thickening of the lung wall. Ullrich et al 45 found that the expression of microRNA(miR)200b in tracheal secretions of fetuses that survived fetoscopic endoluminal tracheal occlusion treatment was higher than that of fetuses that did not respond to tracheal occlusion. The microRNA200 family inhibits several genes in the TGF‐β pathway.…”