The Effect of Exosomes Isolated from Poly (I:C) Treated Human Wharton's Jelly Mesenchymal Stem Cells on CD4+CD25+Foxp3+ Regulatory T Cells
Abstract
Mesenchymal stem cells (MSCs) are a potential cell therapy candidate for autoimmune and inflammatory diseases due to their multilineage capacity and immune modulating function. MSCs exert immunomodulatory effects on target cells through the secretion of exosomes. Inflammatory conditions such as Toll-like receptors (TLRs) engagement can change the biological functions and immunomodulatory activities of MSCs and the contents of exosomes derived from MSCs are changed. Regulatory T-cells (Treg) are crucial for maintaining immune cell homeostasis and self-tolerance. Our study aimed to investigate the impact of isolated exosomes from hWJ-MSCs that were treated with Poly (I:C) on regulatory CD4 CD25 Foxp3 T-cells.
MSCs were harvested from human umbilical cord Wharton’s Jelly by explant method. Stem cells were treated by Polyinosinic-polycytidylic acid sodium salt (Poly (I:C)) for 48 hours. Exosomes were extracted from supernatant of cells and Scanning electron microscopy (SEM) and Dynamic light scattering (DLS) were performed for them. Peripheral blood mononuclear cells (PBMCs) isolated from the healthy donors were stimulated with PHA (Phytohemagglutinin) and co-cultured with Poly (I:C) treated hWJ-MSCs derived exosome and untreated hWJ-MSCs derived exosome or without hWJ-MSCs-derived exosome for 6 days. Then, frequency of CD4+CD25+ Foxp3+ regulatory T cells was measured by flow cytometry.
Our results showed that exosomes isolated from Poly (I:C) treated hWJ-MSCs significantly increased frequency of CD4+CD25+ Foxp3+ regulatory T cells compared to the untreated hWJ-MSCs derived exosome group and control group.
Stimulation by TLR3 improved the anti-inflammatory features of exosomes that were derived from hWJ-MSCs by increasing the frequency of Treg cells.
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22. Ranjbaran H, Abediankenari S, Mohammadi M, Jafari N, Khalilian A, Rahmani Z, et al. Wharton's Jelly Derived-Mesenchymal Stem Cells: Isolation and Characterization. Acta Med Iran. 2018;56(1):28-33..
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27. Chen H, Wang L, Zeng X, Schwarz H, Nanda HS, Peng X, et al. Exosomes , a New Star for Targeted Delivery. Front Cell Dev Biol. 2021;9:751079.
28. Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Boon A, et al. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med. 2011;9(1):47.
29. Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome : a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6(4):481-92.
30. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid A, Mardani K. Microvesicles derived from mesenchymal stem cells : Potent organelles for induction of tolerogenic signaling. Immunol Lett. 2012;147(1–2):47–54.
31. Zhang Q, Fu L, Liang Y, Guo Z,Wang L, Ma C, et al. Exosomes originating from MSCs stimulated with TGF-β and IFN-γ promote Treg differentiation. J Cell Physiol.2018;233(9):6832-40.
32. Qiu Y, Guo J, Mao R, Chao K, Chen B, He Y, et al. TLR3 preconditioning enhances the therapeutic efficacy of umbilical cord mesenchymal stem cells in TNBS-induced colitis via the TLR3-Jagged-1-Notch-1 pathway. Mucosal Immunol. 2017;10(3):727–42.
33. Moeller CJ. Toll-Like Receptor 3 Activator Preconditioning Enhances Modulatory Function of Adipose ‑ Derived Mesenchymal Stem Cells in a Fully MHC-Mismatched Murine Model of Heterotopic Heart Transplantation. Ann Transplant. 2020;25: e921287-1–e921287-11.
34. Fuenzalida P, Kurte M, Ryan CF, Ibañez C, Gauthier-abeliuk M, Vega-letter ANAM, et al. Toll-like receptor 3 pre-conditioning increases the therapeutic efficacy of umbilical cord mesenchymal stromal cells in a dextran sulfate sodium – induced colitis model. Cytotherapy. 2016;18(5):630–41.
35. Lim J, Kim B, Ryu D, Kim TW, Park G, Min C. The therapeutic efficacy of mesenchymal stromal cells on experimental colitis was improved by the IFN- γ and poly (I : C ) priming through promoting the expression of indoleamine 2, 3-dioxygenase. Stem Cell Res Ther. 2021;1–13.
2. Huang Y, Wu Q, Tam PKH. Immunomodulatory Mechanisms of Mesenchymal Stem Cells and Their Potential Clinical Applications. Int J Mol Sci. 2022;23(17):10023.
3. Jasim SA, Yumashev AV, Abdelbasset WK, Margiana R, Markov A, Suksatan W, et al. Shining the light on clinical application of mesenchymal stem cell therapy in autoimmune diseases. Stem Cell Res Ther. 2022;13(1):1–15.
4. Wang M, Yuan Q, Xie L. Mesenchymal stem cell-based immunomodulation: Properties and clinical application. Stem Cells Int. 2018;2018: 3057624.
5. Lee SH. The advantages and limitations of mesenchymal stem cells in clinical application for treating human diseases. Osteoporos Sarcopenia. 2018;4(4):150.
6. Zhu Y, Wang Y, Zhao B, Niu X, Hu B, Li Q, et al. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Res Ther. 2017;8(1):1–11.
7. Liu X, Wei Q, Lu L, Cui S, Ma K, Zhang W, et al. Immunomodulatory potential of mesenchymal stem cell-derived extracellular vesicles : Targeting immune cells. Front Immunol. 2023;14: 1094685.
8. Shen Z, Huang W, Liu J, Tian J, Wang S, Rui K. Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases. Front Immunol. 2021;12:749192.
9. Qian X, An N, Ren Y, Yang C, Zhang X, Li L. Immunosuppressive Effects of Mesenchymal Stem Cells-derived Exosomes. Stem Cell Rev Rep. 2021;17(2):411-27.
10. Li M, Soder R, Abhyankar S, Abdelhakim H, Braun MW, Trinidad C V., et al. WJMSC-derived small extracellular vesicle enhance T cell suppression through PD-L1. J Extra cell Vesicles. 2021;10(4):e12067.
11. Sang H, Zhao R, Lai G, Deng Z, Zhuang W, Wu M, et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate the maturation of dendritic cells and reduce the rejection of allogeneic transplantation. Adv Clin Exp Med. 2023;32(5):551-61.
12. Reis M, Mavin E, Nicholson L, Green K, Dickinson AM, Wang XN. Mesenchymal stromal cell-derived extracellular vesicles attenuate dendritic cell maturation and function. Front Immunol. 2018; 9:2538.
13. Lucca LE, Dominguez-Villar M. Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat Rev Immunol. 2020;20(11):680–93.
14. Meng X, Layhadi JA, Keane ST, Cartwright NJK, Durham SR, Shamji MH. Allergy Immunological mechanisms of tolerance : Central , peripheral and the role of T and B cells. Asia Pac Allergy. 2023;13(4):175–86.
15. Lee BC, Kang KS. Functional enhancement strategies for immunomodulation of mesenchymal stem cells and their therapeutic application. Stem Cell Res Ther. 2020;11(1):1–10.
16. Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol. 2022;13:812774.
17. Najar M, Krayem M, Meuleman N, Bron D, Lagneaux L. Mesenchymal stromal cells and toll-like receptor priming: A critical review. Immune Netw. 2017;17(2):89–102.
18. Cho KA, Park M, Kim YH, Ryu KH, Woo SY. Poly I:C primes the suppressive function of human palatine tonsil-derived MSCs against Th17 differentiation by increasing PD-L1 expression. Immunobiology. 2017;222(2):394–8.
19. Park A, Park H, Yoon J, Kang D, Kang MH, Park YY, et al. Priming with Toll-like receptor 3 agonist or interferon-gamma enhances the therapeutic effects of human mesenchymal stem cells in a murine model of atopic dermatitis. Stem Cell Res Ther. 2019;10(1):1–11.
20. Zhao X, Liu D, Gong W, Zhao G, Liu L, Yang L, et al. The toll-like receptor 3 Ligand, Poly(I:C), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting MiR-143. Stem Cells. 2014;32(2):521–33.
21. Ren K. Exosomes in perspective: a potential surrogate for stem cell therapy. Odontology. 2019;176(5):139–48.
22. Ranjbaran H, Abediankenari S, Mohammadi M, Jafari N, Khalilian A, Rahmani Z, et al. Wharton's Jelly Derived-Mesenchymal Stem Cells: Isolation and Characterization. Acta Med Iran. 2018;56(1):28-33..
23. Lemos VPA, Porto M, Cezar RDAS, Dos BP, Souza MRDE, Silva JDA, et al. Comparison of senescence phenotype of short- and long- term cultured rat mesenchymal stem cells in vitro. An Acad Bras Cienc. 2022;94:e20211246.
24. Kim SH, Yang Y. Recent Advances in Exosome-Based Drug Delivery for Cancer Therapy. Cancers (Basel). 2021;13(17): 4435.
25. Peng Y. Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases : From immunomodulation to therapy. Eur J Immunol. 2023;53(10):e2149510.
26. Xu K, Ma D, Zhang G, Gao J, Su Y, Liu S, et al. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes. Mol Immunol. 2021;135:36-44.
27. Chen H, Wang L, Zeng X, Schwarz H, Nanda HS, Peng X, et al. Exosomes , a New Star for Targeted Delivery. Front Cell Dev Biol. 2021;9:751079.
28. Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Boon A, et al. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med. 2011;9(1):47.
29. Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome : a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6(4):481-92.
30. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid A, Mardani K. Microvesicles derived from mesenchymal stem cells : Potent organelles for induction of tolerogenic signaling. Immunol Lett. 2012;147(1–2):47–54.
31. Zhang Q, Fu L, Liang Y, Guo Z,Wang L, Ma C, et al. Exosomes originating from MSCs stimulated with TGF-β and IFN-γ promote Treg differentiation. J Cell Physiol.2018;233(9):6832-40.
32. Qiu Y, Guo J, Mao R, Chao K, Chen B, He Y, et al. TLR3 preconditioning enhances the therapeutic efficacy of umbilical cord mesenchymal stem cells in TNBS-induced colitis via the TLR3-Jagged-1-Notch-1 pathway. Mucosal Immunol. 2017;10(3):727–42.
33. Moeller CJ. Toll-Like Receptor 3 Activator Preconditioning Enhances Modulatory Function of Adipose ‑ Derived Mesenchymal Stem Cells in a Fully MHC-Mismatched Murine Model of Heterotopic Heart Transplantation. Ann Transplant. 2020;25: e921287-1–e921287-11.
34. Fuenzalida P, Kurte M, Ryan CF, Ibañez C, Gauthier-abeliuk M, Vega-letter ANAM, et al. Toll-like receptor 3 pre-conditioning increases the therapeutic efficacy of umbilical cord mesenchymal stromal cells in a dextran sulfate sodium – induced colitis model. Cytotherapy. 2016;18(5):630–41.
35. Lim J, Kim B, Ryu D, Kim TW, Park G, Min C. The therapeutic efficacy of mesenchymal stromal cells on experimental colitis was improved by the IFN- γ and poly (I : C ) priming through promoting the expression of indoleamine 2, 3-dioxygenase. Stem Cell Res Ther. 2021;1–13.
| Files | ||
| Issue | Vol 23 No 3 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i3.15638 | |
| Keywords | ||
| Exosome Mesenchymal stem cells Regulatory T-cells Toll-like receptor3 | ||
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How to Cite
1.
Misaghian A, Ghadiri AA, Asadirad A, Amirzadeh S, Amari A. The Effect of Exosomes Isolated from Poly (I:C) Treated Human Wharton’s Jelly Mesenchymal Stem Cells on CD4+CD25+Foxp3+ Regulatory T Cells. Iran J Allergy Asthma Immunol. 2024;23(3):288-298.
