Nintedanib-loaded Exosomes from Adipose-derived Stem Cells Inhibit Pulmonary Fibrosis Induced by Bleomycin

Overview

Journal Pediatr Res

Specialties Biology
Pediatrics

Date 2024 Jan 20

PMID 38245633

Authors

Liyun Cai

Jie Wang

Xue Yi

Shuwei Yu

Chong Wang

Liyuan Zhang

Xiaoling Zhang

Lixian Cheng

Wenwen Ruan

Feige Dong

Ping Su

Ying Shi

Affiliations

Soon will be listed here.

Abstract

Background: Pulmonary fibrosis (PF) is a progressive lung disorder with a high mortality rate; its therapy remains limited due to the inefficiency of drug delivery. In this study, the system of drug delivery of nintedanib (Nin) by exosomes derived from adipose-derived stem cells (ADSCs-Exo, Exo) was developed to effectively deliver Nin to lung lesion tissue to ensure enhanced anti-fibrosis therapy.

Methods: The bleomycin (BLM)-induced PF model was constructed in vivo and in vitro. The effects of Exo-Nin on BLM-induced PF and its regulatory mechanism were examined using RT-qPCR, Western blotting, immunofluorescence, and H&E staining.

Results: We found Exo-Nin significantly improved BLM-induced PF in vivo and in vitro compared to Nin and Exo groups alone. Mechanistically, Exo-Nin alleviated fibrogenesis by suppressing endothelial-mesenchymal transition through the down-regulation of the TGF-β/Smad pathway and the attenuation of oxidative stress in vivo and in vitro.

Conclusions: Utilizing adipose stem cell-derived exosomes as carriers for Nin exhibited a notable enhancement in therapeutic efficacy. This improvement can be attributed to the regenerative properties of exosomes, indicating promising prospects for adipose-derived exosomes in cell-free therapies for PF.

Impact: The system of drug delivery of nintedanib (Nin) by exosomes derived from adipose-derived stem cells was developed to effectively deliver Nin to lung lesion tissue to ensure enhanced anti-fibrosis therapy. The use of adipose stem cell-derived exosomes as the carrier of Nin may increase the therapeutic effect of Nin, which can be due to the regenerative properties of the exosomes and indicate promising prospects for adipose-derived exosomes in cell-free therapies for PF.

Citing Articles

Extracellular Vesicles in Idiopathic Pulmonary Fibrosis: Pathogenesis, Biomarkers and Innovative Therapeutic Strategies.

Yang Y, Lv M, Xu Q, Wang X, Fang Z Int J Nanomedicine. 2024; 19:12593-12614.

PMID: 39619058 PMC: 11606342. DOI: 10.2147/IJN.S491335.

Advances in regulating endothelial-mesenchymal transformation through exosomes.

Sishuai S, Lingui G, Pengtao L, Xinjie B, Junji W Stem Cell Res Ther. 2024; 15(1):391.

PMID: 39482726 PMC: 11529026. DOI: 10.1186/s13287-024-04010-w.

Different origin-derived exosomes and their clinical advantages in cancer therapy.

Jin X, Zhang J, Zhang Y, He J, Wang M, Hei Y Front Immunol. 2024; 15:1401852.

PMID: 38994350 PMC: 11236555. DOI: 10.3389/fimmu.2024.1401852.

Mesenchymal stromal cell-based therapy in lung diseases; from research to clinic.

Yuan D, Bao Y, El-Hashash A Am J Stem Cells. 2024; 13(2):37-58.

PMID: 38765802 PMC: 11101986. DOI: 10.62347/JAWM2040.

Molecular Mechanisms Responsible for the Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Lung Fibrosis.

Harrell C, Djonov V, Volarevic A, Arsenijevic A, Volarevic V Int J Mol Sci. 2024; 25(8).

PMID: 38673961 PMC: 11050301. DOI: 10.3390/ijms25084378.

References

Richeldi L, Collard H, Jones M . Idiopathic pulmonary fibrosis. Lancet. 2017; 389(10082):1941-1952. DOI: 10.1016/S0140-6736(17)30866-8. View

Wynn T . Cellular and molecular mechanisms of fibrosis. J Pathol. 2007; 214(2):199-210. PMC: 2693329. DOI: 10.1002/path.2277. View

Wynn T, Ramalingam T . Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012; 18(7):1028-40. PMC: 3405917. DOI: 10.1038/nm.2807. View

Hutchinson J, Fogarty A, Hubbard R, McKeever T . Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 2015; 46(3):795-806. DOI: 10.1183/09031936.00185114. View

McPherson M, Economidou S, Liampas A, Zis P, Parperis K . Management of MDA-5 antibody positive clinically amyopathic dermatomyositis associated interstitial lung disease: A systematic review. Semin Arthritis Rheum. 2022; 53:151959. DOI: 10.1016/j.semarthrit.2022.151959. View

Mohammadalipour A, Hashemnia M, Goudarzi F, Ravan A . Increasing the effectiveness of tyrosine kinase inhibitor (TKI) in combination with a statin in reducing liver fibrosis. Clin Exp Pharmacol Physiol. 2019; 46(12):1183-1193. DOI: 10.1111/1440-1681.13157. View

Neul C, Schaeffeler E, Sparreboom A, Laufer S, Schwab M, Nies A . Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors. Trends Pharmacol Sci. 2016; 37(11):904-932. DOI: 10.1016/j.tips.2016.08.003. View

Ntolios P, Archontogeorgis K, Anevlavis S, Bonelis K, Paxinou N, Voulgaris A . Feasibility and safety of treatment switch from Pirfenidone to Nintedanib in patients with idiopathic pulmonary fibrosis: a real-world observational study. Eur Rev Med Pharmacol Sci. 2021; 25(20):6326-6332. DOI: 10.26355/eurrev_202110_27004. View

Jiang L, Gu Y, Du Y, Tang X, Wu X, Liu J . Engineering Exosomes Endowed with Targeted Delivery of Triptolide for Malignant Melanoma Therapy. ACS Appl Mater Interfaces. 2021; 13(36):42411-42428. DOI: 10.1021/acsami.1c10325. View

10.

Ashour A, El-Kamel A, Mehanna R, Mourad G, A Heikal L . Luteolin-loaded exosomes derived from bone marrow mesenchymal stem cells: a promising therapy for liver fibrosis. Drug Deliv. 2022; 29(1):3270-3280. PMC: 9639476. DOI: 10.1080/10717544.2022.2142700. View

11.

Li J, Huang S, Wu Y, Gu C, Gao D, Feng C . Paracrine factors from mesenchymal stem cells: a proposed therapeutic tool for acute lung injury and acute respiratory distress syndrome. Int Wound J. 2013; 11(2):114-21. PMC: 7950663. DOI: 10.1111/iwj.12202. View

12.

Chen L, Qu J, Kalyani F, Zhang Q, Fan L, Fang Y . Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications. Cell Mol Life Sci. 2022; 79(3):142. PMC: 8858603. DOI: 10.1007/s00018-021-04096-y. View

13.

Wang X, Liu D, Zhang X, Yang L, Xia Z, Zhang Q . Exosomes from adipose-derived mesenchymal stem cells alleviate sepsis-induced lung injury in mice by inhibiting the secretion of IL-27 in macrophages. Cell Death Discov. 2022; 8(1):18. PMC: 8744023. DOI: 10.1038/s41420-021-00785-6. View

14.

Shen W, Zhao X, Li S . Exosomes Derived from ADSCs Attenuate Sepsis-Induced Lung Injury by Delivery of Circ-Fryl and Regulation of the miR-490-3p/SIRT3 Pathway. Inflammation. 2021; 45(1):331-342. DOI: 10.1007/s10753-021-01548-2. View

15.

Estornut C, Milara J, Bayarri M, Belhadj N, Cortijo J . Targeting Oxidative Stress as a Therapeutic Approach for Idiopathic Pulmonary Fibrosis. Front Pharmacol. 2022; 12:794997. PMC: 8815729. DOI: 10.3389/fphar.2021.794997. View

16.

van der Vliet A, Janssen-Heininger Y, Anathy V . Oxidative stress in chronic lung disease: From mitochondrial dysfunction to dysregulated redox signaling. Mol Aspects Med. 2018; 63:59-69. PMC: 6181583. DOI: 10.1016/j.mam.2018.08.001. View

17.

Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt T, Horowitz J . NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med. 2009; 15(9):1077-81. PMC: 2743335. DOI: 10.1038/nm.2005. View

18.

Kilic T, Ciftci O, Cetin A, Kahraman H . Preventive effect of chrysin on bleomycin-induced lung fibrosis in rats. Inflammation. 2014; 37(6):2116-24. DOI: 10.1007/s10753-014-9946-6. View

19.

Wolters P, Collard H, Jones K . Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2013; 9:157-79. PMC: 4116429. DOI: 10.1146/annurev-pathol-012513-104706. View

20.

Gao Z, Zhang C, Xia N, Tian H, Li D, Lin J . Berberine-loaded M2 macrophage-derived exosomes for spinal cord injury therapy. Acta Biomater. 2021; 126:211-223. DOI: 10.1016/j.actbio.2021.03.018. View