The Role of Extracellular Vesicles Derived from MicroRNA-146a–modified Mesenchymal Stem Cells in Modulating Inflammation in Experimental Glenohumeral Osteoarthritis
-
Baotao Cao
,
Guangyuan Liu
,
Kai Gao
,
Wenqi Fan
,
Wei Zhao
,
Baibai Wang
Abstract
Glenohumeral osteoarthritis (GOA) is characterized by chronic inflammation leading to joint damage. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are promising therapies because of their immunomodulatory functions. The anti-inflammatory effects of EVs from human Adipose-derived MSCs (hADSCs) overexpressing microRNA (miR)-146a were investigated in experimental GOA in this study.
hADSCs were transfected with a mimic negative control or miR-146a mimics. GOA was induced in C57/Bl6j mice, and subsequently, the animals were treated intra-articularly with phosphate-buffered saline, miR-146a EVs, or miR-control EVs. The expression of miR-146a and its targeted cytokines interleukin (IL)-4, IL-10, tumor necrosis factor-alpha (TNF-α), IL-17, and interferon-gamma (IFN-γ) were analyzed in the spleen of mice by enzyme-linked immunosorbent assay and in the articular cartilage by real-time polymerase chain reaction.
miR-146a EVs showed enrichment of miR-146a. In GOA mice, miR-146a EV treatment significantly reduced expression levels of inflammatory cytokines IFN-γ, IL-17, and TNF-α and increased the anti-inflammatory cytokine IL-10 and IL-4 compared to controls. miR-146a EV treatment raised the anti-inflammatory cytokines and reduced the pro-inflammatory cytokines of the spleen in treated mice.
This study demonstrates that EVs derived from hADSCs overexpressing miR-146a have enhanced anti-inflammatory potential in GOA by modulating cytokine expression and production. EVs engineered with inflammation-related miRNAs could be a cell-free therapeutic approach for GOA.
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26. Debnath K, Las Heras K, Rivera A, Lenzini S, Shin J-W. Extracellular vesicle–matrix interactions. Nat Rev Mat. 2023;8(6):390-402.
27. Mianehsaz E, Mirzaei HR, Mahjoubin-Tehran M, Rezaee A, Sahebnasagh R, Pourhanifeh MH, et al. Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis? Stem Cell Res Ther. 2019;10:1-13.
28. Jafarinia M, Alsahebfosoul F, Salehi H, Eskandari N, Azimzadeh M, Mahmoodi M, et al. Therapeutic effects of extracellular vesicles from human adipose‐derived mesenchymal stem cells on chronic experimental autoimmune encephalomyelitis. J Cell Physiol. 2020;235(11):8779-90.
29. Ahmadvand Koohsari S, Absalan A, Azadi D. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines. Scientific Rep. 2021;11(1):11658.
30. Chen C, Zhou H, Yin Y, Hu H, Jiang B, Zhang K, et al. Rotator cuff muscle degeneration in a mouse model of glenohumeral osteoarthritis induced by monoiodoacetic acid. J Shoulder Elbow Surg 2023;32(3):500-11.
31. Iacona JR, Lutz CS. miR‐146a‐5p: expression, regulation, and functions in cancer. Wiley Interdisciplinary Reviews: RNA. 2019;10(4):e1533.
32. Chow YY, Chin K-Y. The role of inflammation in the pathogenesis of osteoarthritis. Med Inflamm. 2020;2020.
33. Fei Y, Chaulagain A, Wang T, Chen Y, Liu J, Yi M, et al. MiR-146a down-regulates inflammatory response by targeting TLR3 and TRAF6 in Coxsackievirus B infection. RNA. 2020;26(1):91-100.
34. Feng B, Chen S, Gordon AD, Chakrabarti S. miR-146a mediates inflammatory changes and fibrosis in the heart in diabetes. Journal of molecular and cellular cardiology. 2017;105:70-6.
35. Kong L, Zheng L-Z, Qin L, Ho KK. Role of mesenchymal stem cells in osteoarthritis treatment. J Orthop Translat. 2017;9:89-103.
36. Turturici G, Tinnirello R, Sconzo G, Geraci F. Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. Am J Physiol Cell Physiol. 2014;306(7):C621-C33.
2. Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Gen Med. 2010;26(3):355-69.
3. Kobayashi T, Takagishi K, Shitara H, Ichinose T, Shimoyama D, Yamamoto A, et al. Prevalence of and risk factors for shoulder osteoarthritis in Japanese middle-aged and elderly populations. J Shoulder Elbow Surg. 2014;23(5):613-9.
4. Oh JH, Chung SW, Oh CH, Kim SH, Park SJ, Kim KW, et al. The prevalence of shoulder osteoarthritis in the elderly Korean population: association with risk factors and function. J Shoulder Elbow Surg. 2011;20(5):756-63.
5. Ibounig T, Simons T, Launonen A, Paavola M. Glenohumeral osteoarthritis: an overview of etiology and diagnostics. Scandinavian J Surgery. 2021;110(3):441-51.
6. Uivaraseanu B, Vesa CM, Tit DM, Abid A, Maghiar O, Maghiar TA, et al. Therapeutic approaches in the management of knee osteoarthritis. Exp Ther Med. 2022;23(5):1-6.
7. Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther Adv Musculoskelet Dis. 2013;5(2):77-94.
8. Liu S, Deng Z, Chen K, Jian S, Zhou F, Yang Y, et al. Cartilage tissue engineering: From proinflammatory and anti‑inflammatory cytokines to osteoarthritis treatments. Mol Me Rep. 2022;25(3):1-15.
9. Torensma R, Ter Brugge PJ, Jansen JA, Figdor CG. Ceramic hydroxyapatite coating on titanium implants drives selective bone marrow stromal cell adhesion. Clinl Oral Implants Res. 2003;14(5):569-77.
10. Rostami A, Abbasi Y, Jamalnia S, Asadian A, Enani H, Jafarinia M. Mesenchymal Stem Cells as A New Approach for the Treatment of Multiple Sclerosis: A Literature Review. Galen Med J. 2022;11:e2529.
11. Vohra M, Sharma A, Bagga R, Arora SK. Human umbilical cord-derived mesenchymal stem cells induce tissue repair and regeneration in collagen-induced arthritis in rats. J ClinTrans Res. 2020;6(6):203.
12. Qin L, Liu N, Bao C-l-m, Yang D-z, Ma G-x, Yi W-h, et al. Mesenchymal stem cells in fibrotic diseases—the two sides of the same coin. Acta Pharmacologica Sinica. 2023;44(2):268-87.
13. Jahromi HK, Raberi VS, Moghadam SA, Poudineh M, Barghgir B, Abad MME, et al. Mesenchymal Stromal/Stem Cells in the Tumor Microenvironment and Their Role in Tumor Progression. Galen Med J. 2022;11:e2637-e.
14. Garcia JP, Avila FR, Torres RA, Maita KC, Eldaly AS, Rinker BD, et al. Hypoxia-preconditioning of human adipose-derived stem cells enhances cellular proliferation and angiogenesis: A systematic review. J Clin Trans Res. 2022;8(1):61.
15. Ng J, Little CB, Woods S, Whittle S, Lee FY, Gronthos S, et al. Stem cell-directed therapies for osteoarthritis: the promise and the practice. Stem cells. 2020;38(4):477-86.
16. Dudics V, Kunstár A, Kovács J, Lakatos T, Géher P, Gömör B, et al. Chondrogenic potential of mesenchymal stem cells from patients with rheumatoid arthritis and osteoarthritis: measurements in a microculture system. Cells Tissues Organs. 2009;189(5):307-16.
17. Ruiz M, Cosenza S, Maumus M, Jorgensen C, Noël D. Therapeutic application of mesenchymal stem cells in osteoarthritis. Exp Opin Biol Therapy. 2016;16(1):33-42.
18. Zhang R, Ma J, Han J, Zhang W, Ma J. Mesenchymal stem cell related therapies for cartilage lesions and osteoarthritis. Am J Trans Res. 2019;11(10):6275.
19. Qi Y, Feng G, Yan W. Mesenchymal stem cell-based treatment for cartilage defects in osteoarthritis. Mol Biol Rep. 2012;39:5683-9.
20. Oggu GS, Sasikumar S, Reddy N, Ella KKR, Rao CM, Bokara KK. Gene delivery approaches for mesenchymal stem cell therapy: strategies to increase efficiency and specificity. Stem Cell Rev Rep. 2017;13:725-40.
21. Golabi M, Fathi F, Samadi M, Hesamian MS, Eskandari N. Identification of Potential Biomarkers in the Peripheral Blood Mononuclear Cells of Relapsing–Remitting Multiple Sclerosis Patients. Inflammation. 2022;45(4):1815-28.
22. Kabekkodu SP, Shukla V, Varghese VK, D'Souza J, Chakrabarty S, Satyamoorthy K. Clustered miRNAs and their role in biological functions and diseases. Biol Rev. 2018;93(4):1955-86.
23. Saba R, Sorensen DL, Booth SA. MicroRNA-146a: a dominant, negative regulator of the innate immune response. Front Immunol. 2014;5:578.
24. Zhang Y, Le X, Zheng S, Zhang K, He J, Liu M, et al. MicroRNA-146a-5p-modified human umbilical cord mesenchymal stem cells enhance protection against diabetic nephropathy in rats through facilitating M2 macrophage polarization. Stem Cell Res Ther. 2022;13(1):1-16.
25. Qiu G, Zheng G, Ge M, Wang J, Huang R, Shu Q, et al. Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs. Stem Cell Res Ther 2018;9:1-9.
26. Debnath K, Las Heras K, Rivera A, Lenzini S, Shin J-W. Extracellular vesicle–matrix interactions. Nat Rev Mat. 2023;8(6):390-402.
27. Mianehsaz E, Mirzaei HR, Mahjoubin-Tehran M, Rezaee A, Sahebnasagh R, Pourhanifeh MH, et al. Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis? Stem Cell Res Ther. 2019;10:1-13.
28. Jafarinia M, Alsahebfosoul F, Salehi H, Eskandari N, Azimzadeh M, Mahmoodi M, et al. Therapeutic effects of extracellular vesicles from human adipose‐derived mesenchymal stem cells on chronic experimental autoimmune encephalomyelitis. J Cell Physiol. 2020;235(11):8779-90.
29. Ahmadvand Koohsari S, Absalan A, Azadi D. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines. Scientific Rep. 2021;11(1):11658.
30. Chen C, Zhou H, Yin Y, Hu H, Jiang B, Zhang K, et al. Rotator cuff muscle degeneration in a mouse model of glenohumeral osteoarthritis induced by monoiodoacetic acid. J Shoulder Elbow Surg 2023;32(3):500-11.
31. Iacona JR, Lutz CS. miR‐146a‐5p: expression, regulation, and functions in cancer. Wiley Interdisciplinary Reviews: RNA. 2019;10(4):e1533.
32. Chow YY, Chin K-Y. The role of inflammation in the pathogenesis of osteoarthritis. Med Inflamm. 2020;2020.
33. Fei Y, Chaulagain A, Wang T, Chen Y, Liu J, Yi M, et al. MiR-146a down-regulates inflammatory response by targeting TLR3 and TRAF6 in Coxsackievirus B infection. RNA. 2020;26(1):91-100.
34. Feng B, Chen S, Gordon AD, Chakrabarti S. miR-146a mediates inflammatory changes and fibrosis in the heart in diabetes. Journal of molecular and cellular cardiology. 2017;105:70-6.
35. Kong L, Zheng L-Z, Qin L, Ho KK. Role of mesenchymal stem cells in osteoarthritis treatment. J Orthop Translat. 2017;9:89-103.
36. Turturici G, Tinnirello R, Sconzo G, Geraci F. Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. Am J Physiol Cell Physiol. 2014;306(7):C621-C33.
| Files | ||
| Issue | Vol 23 No 5 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i5.16752 | |
| Keywords | ||
| Exosome Extracellular vesicles Glenohumeral Mesenchymal stem cells Osteoarthritis | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Cao B, Liu G, Gao K, Fan W, Zhao W, Wang B. The Role of Extracellular Vesicles Derived from MicroRNA-146a–modified Mesenchymal Stem Cells in Modulating Inflammation in Experimental Glenohumeral Osteoarthritis. Iran J Allergy Asthma Immunol. 2024;23(5):578-587.
