Overexpression of peroxiredoxin 6 in bone marrow-derived mesenchymal stem cells amplifies their in vivo effect on bronchopulmonary dysplasia by increasing mesencephalic astrocyte-derived neurotrophic factor secretion.

Abstract

Bone marrow-derived mesenchymal stem cell (BMSCs) delivery is a promising therapeutic strategy for bronchopulmonary dysplasia (BPD); however, its efficacy remains suboptimal. Recent studies have reported that extracellular vesicles derived from peroxiredoxin 6 (PRDX6)-downregulated mesenchymal stem cells (MSCs) exhibit diminished anti-inflammatory and anti-oxidant effects through a paracrine mechanism. Nevertheless, whether PRDX6 participates in BPD progression via paracrine signaling remains unclear. Herein, rat BMSCs were first isolated and characterized. The GFP-labeled lentivirus was used to overexpress PRDX6 in BMSCs. PRDX6-overexpressing BMSCs exhibited improved proliferation and migration abilities. Notably, mesencephalic astrocyte-derived neurotrophic factor (MANF) secretion was significantly increased (&#x223c;2.5-fold, p&#xa0;<&#xa0;0.05) in PRDX6-overexpressed BMSCs. Further mechanistic studies revealed that PRDX6 bound to MANF, reducing its endoplasmic reticulum retention by displacing glucose-regulated protein 78, thereby promoting MANF secretion. Silencing MANF expression markedly attenuated the effects of PRDX6 overexpression. PRDX6-modified BMSCs were delivered intratracheally into BPD rat model, which was established by exposing rats in 85&#xa0;% oxygen for 21&#xa0;days. PRDX6 overexpression enhanced BMSCs recruitment to injured lung tissues, and significantly reduced apoptosis, inflammation, vascular loss, and pulmonary arterial remodeling. Concurrently, MANF levels in lung tissues, bronchoalveolar lavage fluid, and serum were elevated post-administration. These results suggest that PRDX6-mediated MANF secretion in BMSCs may not only enhance their proliferative and migratory capacities but also directly protect against lung injury. These findings provide a new strategy for amplifying the in vivo efficacy of BMSCs delivery on BPD.