Prenatal microRNA miR-200b Therapy Improves Nitrofen-induced Pulmonary Hypoplasia Associated With Congenital Diaphragmatic Hernia

Abstract

Our data indicate that miR-200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH.

MicroRNA 200b is upregulated in the lungs of fetal rabbits with surgically induced diaphragmatic hernia

“…Researchers have started to look at expression patterns in specific cell types, which may have further clarified our findings. Our recent study in hypoplastic rat lung explants suggests that disruption in adipocyte differentiation–related protein (marker for lipofibroblasts) in parabronchial mesenchymal cells is associated with lower miR‐200b expression and higher ZEB2 expression in those cells . This is in keeping with studies in human fetal lung explants, where a significant upregulation in the miR‐200 family in type 2 cells during differentiation at mid‐gestation is associated with a subsequent downregulation of ZEB2 and TGF‐β2.…”

“…MiR‐200b knockout mice demonstrate poorer postnatal lung function, reduced surfactant protein, and overall fewer airspaces . Conversely, introduction of miR‐200b mimics in the embryonic stage of lung development to pregnant rats exposed to nitrofen improves survival and reduces the rate of diaphragmatic defects in pups . The miR‐200 family consists of 5 members: miR‐200a, miR‐200b, miR‐429 (chromosome 1) and miR‐200c and miR‐141 (chromosome 12) .…”

“…14 Conversely, introduction of miR-200b mimics in the embryonic stage of lung development to pregnant rats exposed to nitrofen improves survival and reduces the rate of diaphragmatic defects in pups. 15 The miR-200 family consists of 5 members: miR-200a, miR-200b, miR-429 (chromosome 1) and miR-200c and miR-141 (chromosome 12). 16 They regulate ZEB and transforming growth factor-β (TGF-β) via the SMAD pathway and play an important role in pulmonary epithelialmesenchymal transition.…”

“…differentiation-related protein (marker for lipofibroblasts) in parabronchial mesenchymal cells is associated with lower miR-200b expression and higher ZEB2 expression in those cells 15. This is in keeping with studies in human fetal lung explants, where a significant upregulation in the miR-200 family in type 2 cells during differentiation at mid-gestation is associated with a subsequent downregulation29 of ZEB2 and TGF-β2.In control rabbit lungs, there was a trend for higher expression of miR-200b at GD28 (late canalicular/early saccular stage) than at GD23 and lower expression in the alveolar stage.…”

The effects of tracheal occlusion on Wnt signaling in a rabbit model of congenital diaphragmatic hernia

“…Nitrofen administration induces a right or left-sided diaphragmatic defect in 70-80% of fetuses and causes lung hypoplasia in 100% of fetuses [3,6,30,31]. Advantages of the nitrofen-induced CDH rodent model include inexpensive cost and ease of use [3,6].…”