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Published on: June 17, 2016
Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppress Hyperoxia-Induced Transdifferentiation of Rat Alveolar
Danyang Ai1,2, Jieru Shen1,2, Jiali Sun1,2
1Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
Insights
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show promise in preventing bronchopulmonary dysplasia (BPD) in preterm infants. Early administration of MSC-EVs reduced lung injury and fibrosis, potentially by delaying alveolar cell transdifferentiation via WNT5a signaling.
Area of Science:
- Neonatal respiratory medicine
- Stem cell biology
- Regenerative medicine
Background:
- Bronchopulmonary dysplasia (BPD) is a major respiratory complication in preterm infants.
- Current preventive strategies for BPD are limited.
- Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are a potential therapeutic avenue, but optimal regimens and mechanisms are unclear.
Purpose of the Study:
- To investigate the efficacy of early intraperitoneal administration of MSC-EVs in a hyperoxia-induced rat model of BPD.
- To determine the dose-dependent effects of MSC-EVs on lung injury, alveolar development, and vascular complications.
- To elucidate the underlying mechanism of MSC-EVs in preventing BPD, focusing on alveolar epithelial cell transdifferentiation and WNT5a signaling.
Main Methods:
- Establishment of a hyperoxia-induced rat model mimicking BPD.
- Administration of varying doses of MSC-EVs intraperitoneally.
- Assessment of lung injury, alveolar structure, fibrosis, vascular growth, and pulmonary hypertension.
- In vitro study of primary AT2 cell transdifferentiation under hyperoxia.
- Analysis of WNT5a mRNA and protein expression.
Main Results:
- MSC-EVs ameliorated hyperoxia-induced lung injury in a dose-dependent manner.
- High-dose MSC-EVs improved alveolar simplification and reduced lung fibrosis.
- MSC-EVs positively impacted vascular growth and mitigated pulmonary hypertension.
- MSC-EVs delayed the hyperoxia-induced transdifferentiation of primary AT2 cells in vitro.
- MSC-EVs downregulated the expression of WNT5a, a key factor in AT2 cell transdifferentiation.
Conclusions:
- Early intraperitoneal administration of MSC-EVs is a promising preclinical therapeutic strategy for BPD.
- MSC-EVs exert protective effects through dose-dependent amelioration of lung injury, fibrosis, and vascular complications.
- MSC-EVs may prevent BPD by suppressing AT2 cell transdifferentiation, potentially via downregulation of WNT5a signaling.
Abstract:
Bronchopulmonary dysplasia (BPD) remains the most important respiratory morbidity of preterm infants with few effective preventive strategies. Administration of mesenchymal stem cells (MSC) was considered effective to prevent BPD via paracrine extracellular vesicles (EVs), while appropriate regimens of MSC-EVs and the mechanism remain unclear. Therefore, we established a hyperoxia-induced rat BPD model, and examined the effect of early intraperitoneal MSC-EVs with different doses on BPD. We found that MSC-EVs ameliorated hyperoxia-induced lung injury in a dose-dependent manner, and high-dose MSC-EVs ameliorated alveolar simplification and fibrosis. Also, MSC-EVs showed its beneficial effects on vascular growth and pulmonary hypertension. Primary AT2 cells were observed to transdifferentiate into AT1 cells when exposure to hyperoxia in vitro. Administration of MSC-EVs at the first-day culture significantly delayed the transdifferentiation of AT2 cells induced by hyperoxia. We further found that exposure to hyperoxia led to elevated expression of WNT5a mRNA and protein, a key agent in AT2 transdifferentiation, while MSC-EVs administration decreased it. Further study is warranted that MSC-EVs may delay the transdifferentiation of AT2 cells via WNT5a. These studies provide key preclinical evidence of MSC-EVs therapeutics on BPD and highlight the effect of MSC-EVs on suppressing the transdifferentiation of AT2 cells and its possible mechanism through downregulation of WNT5a.
