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HucMSCs-derived Exosomes Promote Lung Development in Premature Birth via Wnt5a/ROCK1 Axis
Xin Li1,2,3,4,5,6, Lidong Huang7, Min Mao1,2,3,4,5,6
1Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China.
Insights
Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSCs-Exos) from full-term infants promote fetal lung development. These exosomes enhance alveolarization, potentially reducing bronchopulmonary dysplasia (BPD) in premature infants.
Area of Science:
- Regenerative Medicine
- Developmental Biology
- Neonatal Research
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting preterm infants, with limited treatment options.
- Improving lung development and repair in premature neonates is critical for managing BPD.
- Current BPD treatments lack specificity and targeted therapeutic approaches.
Purpose of the Study:
- To investigate the potential of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-Exos) to enhance fetal lung development.
- To compare the efficacy of exosomes from full-term versus preterm infants in promoting lung development.
- To elucidate the molecular mechanisms by which hucMSCs-Exos influence alveolarization.
Main Methods:
- hucMSCs-Exos were isolated via ultracentrifugation and characterized using TEM, flow cytometry, WB, and NTA.
- Exosomes were administered to pregnant mice, and embryonic lung tissues were analyzed at E13.5 and E18.5.
- Techniques included HE staining, immunofluorescence, TEM, proteomic analysis, and Western blot (WB).
Main Results:
- Exosomes from full-term infants showed greater efficacy in promoting fetal lung cell proliferation compared to those from preterm infants.
- In vivo administration of full-term hucMSCs-Exos significantly improved alveolarization in embryonic mouse lungs.
- Proteomic analysis identified Wnt5a as highly expressed in full-term exosomes, with evidence of Wnt5a-ROCK1 interaction and increased autophagy marker LC3B.
Conclusions:
- Term hucMSCs-Exos promote fetal lung alveolarization by delivering Wnt5a, which regulates ROCK1 phosphorylation and enhances AT2 cell autophagy.
- This mechanism supports lamellar body development, ultimately improving alveolar structure and potentially reducing BPD incidence.
- hucMSCs-Exos represent a promising cell-free therapeutic strategy for enhancing lung development in premature infants.
Abstract:
Bronchopulmonary dysplasia (BPD) frequently affects extremely preterm and low birth weight infants, with current treatments lacking specificity. Enhancing extra-uterine preterm alveoli development and repairing damage are crucial for BPD management. Here we show that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-Exos) can enhance fetal lung development in mice by delivering specific contents. Briefly, hucMSCs-Exos were extracted using ultracentrifugation and identified by transmission electron microscopy (TEM), flow cytometry, Western blot (WB), and nanoparticle tracking analysis (NTA). These exosomes were then administered to pregnant mice via tail vein injection. Embryonic lung tissues were collected at E13.5 and E18.5 via cesarean section and analyzed using hematoxylin-eosin (HE) staining, immunofluorescence, and TEM. Proteomic analysis was conducted to identify protein components in the exosomes, and WB was used to assess protein expression changes. hucMSCs-Exos from full-term infants were more effective in promoting cell proliferation than those from preterm infants. In vivo, full-term hucMSCs-Exos significantly enhanced alveolarization in fetal lung tissues. Proteomic analysis revealed higher Wnt5a expression in full-term hucMSCs-Exos, and further experiments confirmed a direct interaction between Wnt5a and ROCK1. WB also showed increased expression of the autophagy marker LC3B in the lung tissues of mice treated with full-term exosomes. In conclusion, term hucMSCs-Exos may directly regulate the phosphorylation of ROCK1 in mouse lung tissue through naturally enriched Wnt5a, thus promoting autophagy of AT2 cells and lamellar body development, and ultimately enhance the alveolarization and reducing the incidence of BPD in premature infants.
