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"INTRODUCTION: Bronchopulmonary Dysplasia (BPD) is a life-threatening disorder affecting premature newborns, for which no definite cure is available1,2. Lung fibrosis is one of the main problems that affect young patients. The aim of this work was to investigate the mechanism of action of human extracellular vesicles (EVs) both in vitro and in an animal model of hyperoxia-induced BPD. Specifically, we evaluated the effects of EVs on the development of fibrosis and on functionality of lung epithelial cells.
METHODOLOGY: GMP-grade EVs were produced by human Wharton-Jelly derived MSCs (Exo Biologics, Belgium), isolated by tangential flow filtration and characterized according to MISEV2018. Rat pups were divided in 3 groups: normoxia + PBS vehicle (control group), hyperoxia with PBS (untreated), hyperoxia with MSC EVs in PBS (treated). Both PBS and EVs were injected intratracheally (IT) on day 3, 7 and 10 and pups were sacrified on day 14. The expression of the genes TGFβ1 and aSMA was analysed in lungs. To evaluate epithelial secretory function, the expression of glycosaminoglycans (Alcian blue staining) and of surfactant protein C (SFTPC) was analyzed by histology and immunofluorescence. Collagen deposition was assessed by Sirius Red staining. Macrophages from rat bone marrow were treated with TGFβ, cultured and analyzed for aSMA and CD90 expression by flow cytometry.
RESULTS: Pups under hyperoxia exhibited an increase in collagen deposition in the lungs. This parameter was reduced by treatment with MSC EVs. The area of lung tissue expressing glycosaminoglycans was significantly increased in MSC EV-treated rat pups in respect to untreated animals. In addition, cells expressing SFTPC were significantly increased in MSC EVs treated pups with respect to the untreated group. In vitro, MSC EVs suppressed the induction of aSMA expression in macrophages.
CONCLUSIONS: Intratracheal administration of clinical-grade MSC-EVs counteracts the development of fibrosis and improve pulmonary epithelial function in a neonatal model of hyperoxia-induced lung injury. These results can contribute to understand the mechanism of action of these nanoparticles in preventing the development of BPD.
1- Porzionato, A. et al., Am J Physiol Lung Cell Mol Physiol 316: L6–L19, (2019)
2- Hansmann, G. et al., Pediatric Research 89:446 – 455, (2021)"
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