Safety, Efficacy and Bio-Distribution Analysis of Exosomes Derived From Human Umbilical Cord Mesenchymal Stem Cells for Effective Treatment of Bronchopulmonary Dysplasia by Intranasal Administration in Mice Model

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2025 Mar 4

PMID 40034220

Authors

Wanting Xu

Xiaolin Jieda

Yue Wu

Fengling Du

Lu Ma

Lijuan Luo

Dong Liu

Ling Guo

Jing Liu

Wenbin Dong

Affiliations

Soon will be listed here.

Abstract

Purpose: Exosomes (Exos) derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) hold great potential for treating bronchopulmonary dysplasia (BPD); however, safety concerns and effects of intranasal administration remain unexplored. This study aimed to explore the safety of hUC-MSCs and Exos and to investigate the efficacy and bio-distribution of repeated intranasal Exos administration in neonatal BPD models.

Methods: Characteristics of hUC-MSCs and Exos were analyzed. A subcutaneous tumor formation assay using a single dose of hUC-MSCs or Exos was conducted in Crl:NU-Foxn1nu mice. Vital signs, biochemical indices, pathological alterations, and F-FDG microPET/CT analysis were examined. Pulmonary pathology, three-dimensional reconstructions, ultrastructural structures, in vivo and ex vivo bio-distribution imaging analyses, enzyme-linked immunoassay assays, and reverse transcription-quantitative polymerase chain reaction analyses of lung tissues were all documented following intranasal Exos administration.

Results: Characteristics of hUC-MSCs and Exos satisfied specifications. Crl:NU-Foxn1nu mice did not exhibit overt toxicity or carcinogenicity following a single dose of hUC-MSCs or Exos after 60 days of observation. Repeated intranasal Exos administration effectively alleviated pathological injuries, restored pulmonary ventilation in three-dimensional reconstruction, and recovered endothelial cell layer integrity in ultrastructural analysis. Exos steadily accumulated in lung tissues from postnatal day 1 to 14. Exos also interrupted the epithelial-mesenchymal transition and inflammation reactions in BPD models.

Conclusion: As a nanoscale, non-cellular therapy, intranasal administration of Exos was an effective, noninvasive treatment for BPD. This approach was free from toxic, tumorigenic risks and repaired alveolar damage while interrupting epithelial-mesenchymal transition and inflammation in neonatal mice with BPD.

References

Saneh H, Wanczyk H, Walker J, Finck C . Effectiveness of extracellular vesicles derived from hiPSCs in repairing hyperoxia-induced injury in a fetal murine lung explant model. Stem Cell Res Ther. 2024; 15(1):80. PMC: 10941466. DOI: 10.1186/s13287-024-03687-3. View

Zhong X, Hao T, Zhu Q, Zheng J, Zheng M, Li X . Umbilical cord blood exosomes from very preterm infants with bronchopulmonary dysplasia aggravate lung injury in mice. Sci Rep. 2023; 13(1):8648. PMC: 10224930. DOI: 10.1038/s41598-023-35620-8. View

Chen C, Jin Y, Jin H, Chen S, Wang L, Ji L . Adipose mesenchymal stem cells-derived exosomes attenuated hyperoxia-induced lung injury in neonatal rats via inhibiting the NF-κB signaling pathway. Pediatr Pulmonol. 2024; 59(10):2523-2534. DOI: 10.1002/ppul.27057. View

Li L, Zhang X, Chen Y . Human Umbilical Cord Mesenchymal Stem Cell Exosome-derived miR-335-5p Alleviated Lipopolysaccharide-induced Acute Lung Injury by Regulating the m6A Level of ITGβ4 Gene. Curr Med Chem. 2024; 31(33):5448-5467. DOI: 10.2174/0109298673273833231220062213. View

Zhu Y, Shi M, Monsel A, Dai C, Dong X, Shen H . Nebulized exosomes derived from allogenic adipose tissue mesenchymal stromal cells in patients with severe COVID-19: a pilot study. Stem Cell Res Ther. 2022; 13(1):220. PMC: 9135389. DOI: 10.1186/s13287-022-02900-5. View

Recica R, Kryeziu I, Thaci Q, Avtanski D, Mladenov M, Basholli-Salihu M . Protective Effects of Resveratrol Against Airway Hyperreactivity, Oxidative Stress, and Lung Inflammation in a Rat Pup Model of Bronchopulmonary Dysplasia. Physiol Res. 2024; 73(2):239-251. PMC: 11081184. View

Costa-Ferro Z, Rocha G, da Silva K, Paredes B, Loiola E, Silva J . GMP-compliant extracellular vesicles derived from umbilical cord mesenchymal stromal cells: manufacturing and pre-clinical evaluation in ARDS treatment. Cytotherapy. 2024; 26(9):1013-1025. DOI: 10.1016/j.jcyt.2024.04.074. View

Fontijn S, Balink S, Bonte M, Andrinopoulou E, Duijts L, Kroon A . Chest computed tomography in severe bronchopulmonary dysplasia: Comparing quantitative scoring methods. Eur J Radiol. 2023; 169:111168. DOI: 10.1016/j.ejrad.2023.111168. View

Wang J, Zhang A, Huang F, Xu J, Zhao M . MSC-EXO and tempol ameliorate bronchopulmonary dysplasia in newborn rats by activating HIF-1α. Pediatr Pulmonol. 2023; 58(5):1367-1379. DOI: 10.1002/ppul.26317. View

10.

Guo H, Huang R, Qu S, Yao Y, Chen S, Ding S . FAM134B deletion exacerbates apoptosis and epithelial-to-mesenchymal transition in rat lungs exposed to hyperoxia. iScience. 2024; 27(7):110385. PMC: 11292547. DOI: 10.1016/j.isci.2024.110385. View

11.

Wang X, Cui L, Wang Y, Zeng Z, Wang H, Tian L . Mechanistic investigation of wogonin in delaying the progression of endothelial mesenchymal transition by targeting the TGF-β1 pathway in pulmonary hypertension. Eur J Pharmacol. 2024; 978:176786. DOI: 10.1016/j.ejphar.2024.176786. View

12.

Roeder F, Ropke T, Steinmetz L, Kolb M, Maus U, Smith B . Exploring alveolar recruitability using positive end-expiratory pressure in mice overexpressing TGF-β1: a structure-function analysis. Sci Rep. 2024; 14(1):8080. PMC: 10998853. DOI: 10.1038/s41598-024-58213-5. View

13.

Sucre J, Vickers K, Benjamin J, Plosa E, Jetter C, Cutrone A . Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A. Am J Respir Crit Care Med. 2020; 201(10):1249-1262. PMC: 7233334. DOI: 10.1164/rccm.201908-1513OC. View

14.

Goryunov K, Ivanov M, Kulikov A, Shevtsova Y, Burov A, Podurovskaya Y . A Review of the Use of Extracellular Vesicles in the Treatment of Neonatal Diseases: Current State and Problems with Translation to the Clinic. Int J Mol Sci. 2024; 25(5). PMC: 10932115. DOI: 10.3390/ijms25052879. View

15.

Huang Y, Wu Q, Tam P . Immunomodulatory Mechanisms of Mesenchymal Stem Cells and Their Potential Clinical Applications. Int J Mol Sci. 2022; 23(17). PMC: 9456387. DOI: 10.3390/ijms231710023. View

16.

Goodwin A, John A, Joseph C, Habgood A, Tatler A, Susztak K . Stretch regulates alveologenesis and homeostasis via mesenchymal Gαq/11-mediated TGFβ2 activation. Development. 2023; 150(9). PMC: 10259661. DOI: 10.1242/dev.201046. View

17.

Ren J, Liu Y, Yao Y, Feng L, Zhao X, Li Z . Intranasal delivery of MSC-derived exosomes attenuates allergic asthma via expanding IL-10 producing lung interstitial macrophages in mice. Int Immunopharmacol. 2020; 91:107288. DOI: 10.1016/j.intimp.2020.107288. View

18.

Eldredge L, Creasy R, Presnell S, Debley J, Juul S, Mayock D . Infants with evolving bronchopulmonary dysplasia demonstrate monocyte-specific expression of IL-1 in tracheal aspirates. Am J Physiol Lung Cell Mol Physiol. 2019; 317(1):L49-L56. DOI: 10.1152/ajplung.00060.2019. View

19.

Albertine K, Rebentisch A, Dawson E, Van Boerum J, Major E, Stipka J . Mesenchymal stromal cell extracellular vesicles improve lung development in mechanically ventilated preterm lambs. Am J Physiol Lung Cell Mol Physiol. 2024; 326(6):L770-L785. PMC: 11380989. DOI: 10.1152/ajplung.00349.2023. View

20.

El Azzouzi M, El Ahanidi H, Hassan I, Tetou M, Ameur A, Bensaid M . Comprehensive behavioural assessment of TERT in bladder cancer. Urol Oncol. 2024; 42(12):451.e19-451.e29. DOI: 10.1016/j.urolonc.2024.06.024. View