Exosomes from Adipose Tissue-derived Mesenchymal Stem Cells Induce Regulatory T Cells in COVID‐19 Patients
-
Morteza Motallebnezhad
,
Ali Hazrati
,
Hadi Esmaeili Gouvarchin Ghaleh
,
Nematollah Jonaidi-Jafari
,
Sanaz Abbaspour-Aghdam
,
Kosar Malekpour
,
Mehdi Yousefi
,
Hossein Samadi Kafil
,
Farhad Jadidi-Niaragh
,
Leila Roshangar
,
Hamed Valizadeh
,
Morteza Izadi
,
Majid Ahmadi
Abstract
An imbalance between regulatory T (Treg) and T-helper (Th)-17 cells has been implicated in the pathogenesis of coronavirus disease 2019 (COVID-19). Mesenchymal stem cells (MSCs) exert immunomodulatory properties through secreting exosomes. This study aimed to assess the effect of MSC-derived exosomes (MSC-Exo) on the differentiation of peripheral blood mononuclear cells (PBMCs) into Tregs from patients with COVID-19.
Exosomes were isolated from adipose tissue–derived MSCs. PBMCs were separated from the whole blood of COVID-19 patients (n=20). Treg frequency was assessed before and 48 hours after treatment of PBMCs with MSC-Exo using flow cytometry. Expression of FOXP3 and cytokine genes, and the concentration of cytokines associated with Tregs, were assessed before and after treatment with MSC-Exo.
The frequency of CD4+CD25+CD127- Tregs was significantly higher after treating PBMCs with MSC-Exo (6.695±2.528) compared to before treatment (4.981±2.068). The expressions of transforming growth factor (TGF)-β1, interleukin (IL)-10, and FOXP3 were significantly upregulated in MSC-Exo–treated PBMCs. The concentration of IL‐10 increased significantly after treatment (994.7±543.9 pg/mL) of PBMCs with MSC-Exo compared with before treatment (563.5±408.6 pg/mL). The concentration of TGF-β was significantly higher in the supernatant of PBMCs after treatment with MSC-Exo (477.0±391.1 pg/mL) than PBMCs before treatment (257.7±226.3 pg/mL).
MSC-Exo has the potential to raise anti-inflammatory responses by induction of Tregs, potentiating its therapeutic effects in COVID-19.
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8. Martonik D, Parfieniuk-Kowerda A, Rogalska M, Flisiak R. The Role of Th17 Response in COVID-19. Cells. 2021;10(6):1550.
9. Wing JB, Tanaka A, Sakaguchi S. Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity. 2019;50(2):302-16.
10. Josefowicz SZ, Lu L-F, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531-64.
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14. Zachar L, Bačenková D, Rosocha J. Activation, homing, and role of the mesenchymal stem cells in the inflammatory environment. J Inflamm Res. 2016;9:231.
15. Yan Z, Zhuansun Y, Chen R, Li J, Ran P. Immunomodulation of mesenchymal stromal cells on regulatory T cells and its possible mechanism. Exp Cell Res. 2014;324(1):65-74.
16. Chen Q-H, Wu F, Liu L, Chen H-b, Zheng R-Q, Wang H-L, et al. Mesenchymal stem cells regulate the Th17/ Treg balance partly through hepatocyte growth factor in vitro. Stem Cell Res Ther. 2020;11(1):1-11.
17. Lee SH. The advantages and limitations of mesenchymal stem cells in clinical application for treating human diseases. Osteoporosis Sarcopenia. 2018;4(4):150.
18. Malekpour K, Hazrati A, Zahar M, Markov A, Zekiy AO, Navashenaq JG, et al. The Potential Use of Mesenchymal Stem Cells and Their Derived Exosomes for Orthopedic Diseases Treatment. Stem Cell Rev Rep. 2021:1-19.
19. Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell & bioscience. 2019;9(1):1-18.
20. Weiliang Z, Lili G. Research Advances in the Application of Adipose-Derived Stem Cells Derived Exosomes in Cutaneous Wound Healing. Ann Dermatol. 2021;33(4):309-17.
21. Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunologic Res. 2016;64(4):831-40.
22. Alipoor SD, Mortaz E, Garssen J, Movassaghi M, Mirsaeidi M, Adcock IM. Exosomes and exosomal miRNA in respiratory diseases. Med Inflammation. 2016;2016.
23. Du Y-m, Zhuansun Y-x, Chen R, Lin L, Lin Y, Li J-g. Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. Exp Cell Res. 2018;363(1):114-20.
24. Rezakhani L, Kelishadrokhi AF, Soleimanizadeh A. Mesenchymal stem cell (MSC)-derived exosomes as a cell-free therapy for patients Infected with COVID-19: Real opportunities and range of promises. Chem Phys Lipids. 2020:105009.
25. Jafarpour M, Omidvar MH, Soltani-Zangbar MS, Dolati S, Ahmadi M, Jadidi-Niaragh F, et al. The effects of PBMCs-derived exosomes of ankylosing spondylitis patients on T cell profiles. Gene Reports. 2022;26:101446.
26. Sadeghzadeh-Bazargan A, Behrangi E, Goodarzi A. Cytokine storm and probable role of immunoregulatory drugs in COVID-19: a comprehensive review. Iran J Dermatol. 2020;23(Suppl. 1 (COVID-19)):13-8.
27. Murphy KM, Ouyang W, Farrar JD, Yang J, Ranganath S, Asnagli H, et al. Signaling and transcription in T helper development. Ann Rev Immunol. 2000;18(1):451-94.
28. Bedoya SK, Lam B, Lau K, Larkin J. Th17 cells in immunity and autoimmunity. Clin Dev Immunol. 2013;2013.
29. Sadeghi A, Tahmasebi S, Mahmood A, Kuznetsova M, Valizadeh H, Taghizadieh A, et al. Th17 and Tregs function in SARS‐CoV2 patients compared with healthy controls. J Cell Physiol. 2021;236(4):2829-39.
30. Lin S, Wu H, Wang C, Xiao Z, Xu F. Regulatory T cells and acute lung injury: cytokines, uncontrolled inflammation, and therapeutic implications. Front Immunol. 2018;9:1545.
31. Yu Z-x, Ji M-s, Yan J, Cai Y, Liu J, Yang H-f, et al. The ratio of Th17/ Tregs as a risk indicator in early acute respiratory distress syndrome. Critical Care. 2015;19(1):1-11.
32. Muyayalo KP, Huang DH, Zhao SJ, Xie T, Mor G, Liao AH. COVID‐19 and Treg/Th17 imbalance: Potential relationship to pregnancy outcomes. Am J Reprod Immunol. 2020;84(5):e13304.
33. Ding D-C, Shyu W-C, Lin S-Z. Mesenchymal stem cells. Cell transplantation. 2011;20(1):5-14.
34. Saldaña L, Bensiamar F, Vallés G, Mancebo FJ, García-Rey E, Vilaboa N. Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res Ther. 2019;10(1):1-15.
35. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell stem cell. 2013;13(4):392-402.
36. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8(4):420-2.
37. Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014;15(3):4142-57.
38. Metcalfe SM. Mesenchymal stem cells and management of COVID-19 pneumonia. Med Drug Discovery. 2020;5:100019.
39. Liu S, Peng D, Qiu H, Yang K, Fu Z, Zou L. Mesenchymal stem cells as a potential therapy for COVID-19. Stem cell ResTherapy. 2020;11(1):1-4.
40. Yousefi Dehbidi M, Goodarzi N, Azhdari MH, Doroudian M. Mesenchymal stem cells and their derived exosomes to combat Covid–19. Rev Med Virology. 2022;32(2):e2281.
41. Dauletova M, Hafsan H, Mahhengam N, Zekiy AO, Ahmadi M, Siahmansouri H. Mesenchymal stem cell alongside exosomes as a novel cell-based therapy for COVID-19: A review study. Clin Immunol. 2021:108712.
42. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem cells and development. 2020;29(12):747-54.
43. Cho BS, Kim JO, Ha DH, Yi YW. Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. Stem Cells Dev. 2018;9(1):1-5.
44. Nojehdehi S, Soudi S, Hesampour A, Rasouli S, Soleimani M, Hashemi SM. Immunomodulatory effects of mesenchymal stem cell–derived exosomes on experimental type‐1 autoimmune diabetes. J Cell Biochem. 2018;119(11):9433-43.
45. Zhao H, Shang Q, Pan Z, Bai Y, Li Z, Zhang H, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes. 2018;67(2):235-47.
46. Taghavi-Farahabadi M, Mahmoudi M, Rezaei N, Hashemi SM. Wharton’s Jelly Mesenchymal Stem cells exosomes and conditioned media increased Neutrophil lifespan and phagocytosis capacity. Immunol Investigations. 2021;50(8):1042-57.
2. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565-74.
3. Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20(5):269-70.
4. Rana MM. Cytokine storm in COVID-19: Potential therapeutics for immunomodulation. J Res Clin Med. 2020;8(1):38-.
5. Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020;181(4):894-904. e9.
6. Zhao J, He S, Minassian A, Li J, Feng P. Recent advances on viral manipulation of NF-κB signaling pathway. Curr Opin Virol. 2015;15:103-11.
7. Wu C, Chen X, Cai Y, Zhou X, Xu S, Huang H, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-43.
8. Martonik D, Parfieniuk-Kowerda A, Rogalska M, Flisiak R. The Role of Th17 Response in COVID-19. Cells. 2021;10(6):1550.
9. Wing JB, Tanaka A, Sakaguchi S. Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity. 2019;50(2):302-16.
10. Josefowicz SZ, Lu L-F, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531-64.
11. Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, et al. A distinct function of regulatory T cells in tissue protection. Cell. 2015;162(5):1078-89.
12. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9.
13. Stephen-Victor E, Das M, Karnam A, Pitard B, Gautier J-F, Bayry J. Potential of regulatory T-cell-based therapies in the management of severe COVID-19. Eur Respir J. 2020;56(3).
14. Zachar L, Bačenková D, Rosocha J. Activation, homing, and role of the mesenchymal stem cells in the inflammatory environment. J Inflamm Res. 2016;9:231.
15. Yan Z, Zhuansun Y, Chen R, Li J, Ran P. Immunomodulation of mesenchymal stromal cells on regulatory T cells and its possible mechanism. Exp Cell Res. 2014;324(1):65-74.
16. Chen Q-H, Wu F, Liu L, Chen H-b, Zheng R-Q, Wang H-L, et al. Mesenchymal stem cells regulate the Th17/ Treg balance partly through hepatocyte growth factor in vitro. Stem Cell Res Ther. 2020;11(1):1-11.
17. Lee SH. The advantages and limitations of mesenchymal stem cells in clinical application for treating human diseases. Osteoporosis Sarcopenia. 2018;4(4):150.
18. Malekpour K, Hazrati A, Zahar M, Markov A, Zekiy AO, Navashenaq JG, et al. The Potential Use of Mesenchymal Stem Cells and Their Derived Exosomes for Orthopedic Diseases Treatment. Stem Cell Rev Rep. 2021:1-19.
19. Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell & bioscience. 2019;9(1):1-18.
20. Weiliang Z, Lili G. Research Advances in the Application of Adipose-Derived Stem Cells Derived Exosomes in Cutaneous Wound Healing. Ann Dermatol. 2021;33(4):309-17.
21. Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunologic Res. 2016;64(4):831-40.
22. Alipoor SD, Mortaz E, Garssen J, Movassaghi M, Mirsaeidi M, Adcock IM. Exosomes and exosomal miRNA in respiratory diseases. Med Inflammation. 2016;2016.
23. Du Y-m, Zhuansun Y-x, Chen R, Lin L, Lin Y, Li J-g. Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. Exp Cell Res. 2018;363(1):114-20.
24. Rezakhani L, Kelishadrokhi AF, Soleimanizadeh A. Mesenchymal stem cell (MSC)-derived exosomes as a cell-free therapy for patients Infected with COVID-19: Real opportunities and range of promises. Chem Phys Lipids. 2020:105009.
25. Jafarpour M, Omidvar MH, Soltani-Zangbar MS, Dolati S, Ahmadi M, Jadidi-Niaragh F, et al. The effects of PBMCs-derived exosomes of ankylosing spondylitis patients on T cell profiles. Gene Reports. 2022;26:101446.
26. Sadeghzadeh-Bazargan A, Behrangi E, Goodarzi A. Cytokine storm and probable role of immunoregulatory drugs in COVID-19: a comprehensive review. Iran J Dermatol. 2020;23(Suppl. 1 (COVID-19)):13-8.
27. Murphy KM, Ouyang W, Farrar JD, Yang J, Ranganath S, Asnagli H, et al. Signaling and transcription in T helper development. Ann Rev Immunol. 2000;18(1):451-94.
28. Bedoya SK, Lam B, Lau K, Larkin J. Th17 cells in immunity and autoimmunity. Clin Dev Immunol. 2013;2013.
29. Sadeghi A, Tahmasebi S, Mahmood A, Kuznetsova M, Valizadeh H, Taghizadieh A, et al. Th17 and Tregs function in SARS‐CoV2 patients compared with healthy controls. J Cell Physiol. 2021;236(4):2829-39.
30. Lin S, Wu H, Wang C, Xiao Z, Xu F. Regulatory T cells and acute lung injury: cytokines, uncontrolled inflammation, and therapeutic implications. Front Immunol. 2018;9:1545.
31. Yu Z-x, Ji M-s, Yan J, Cai Y, Liu J, Yang H-f, et al. The ratio of Th17/ Tregs as a risk indicator in early acute respiratory distress syndrome. Critical Care. 2015;19(1):1-11.
32. Muyayalo KP, Huang DH, Zhao SJ, Xie T, Mor G, Liao AH. COVID‐19 and Treg/Th17 imbalance: Potential relationship to pregnancy outcomes. Am J Reprod Immunol. 2020;84(5):e13304.
33. Ding D-C, Shyu W-C, Lin S-Z. Mesenchymal stem cells. Cell transplantation. 2011;20(1):5-14.
34. Saldaña L, Bensiamar F, Vallés G, Mancebo FJ, García-Rey E, Vilaboa N. Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res Ther. 2019;10(1):1-15.
35. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell stem cell. 2013;13(4):392-402.
36. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8(4):420-2.
37. Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014;15(3):4142-57.
38. Metcalfe SM. Mesenchymal stem cells and management of COVID-19 pneumonia. Med Drug Discovery. 2020;5:100019.
39. Liu S, Peng D, Qiu H, Yang K, Fu Z, Zou L. Mesenchymal stem cells as a potential therapy for COVID-19. Stem cell ResTherapy. 2020;11(1):1-4.
40. Yousefi Dehbidi M, Goodarzi N, Azhdari MH, Doroudian M. Mesenchymal stem cells and their derived exosomes to combat Covid–19. Rev Med Virology. 2022;32(2):e2281.
41. Dauletova M, Hafsan H, Mahhengam N, Zekiy AO, Ahmadi M, Siahmansouri H. Mesenchymal stem cell alongside exosomes as a novel cell-based therapy for COVID-19: A review study. Clin Immunol. 2021:108712.
42. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem cells and development. 2020;29(12):747-54.
43. Cho BS, Kim JO, Ha DH, Yi YW. Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. Stem Cells Dev. 2018;9(1):1-5.
44. Nojehdehi S, Soudi S, Hesampour A, Rasouli S, Soleimani M, Hashemi SM. Immunomodulatory effects of mesenchymal stem cell–derived exosomes on experimental type‐1 autoimmune diabetes. J Cell Biochem. 2018;119(11):9433-43.
45. Zhao H, Shang Q, Pan Z, Bai Y, Li Z, Zhang H, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes. 2018;67(2):235-47.
46. Taghavi-Farahabadi M, Mahmoudi M, Rezaei N, Hashemi SM. Wharton’s Jelly Mesenchymal Stem cells exosomes and conditioned media increased Neutrophil lifespan and phagocytosis capacity. Immunol Investigations. 2021;50(8):1042-57.
| Files | ||
| Issue | Vol 22 No 3 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i3.13051 | |
| Keywords | ||
| COVID-19 Exosomes Immunomodulation Mesenchymal stem cells Peripheral blood mononuclear cells Regulatory T cells | ||
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How to Cite
1.
Motallebnezhad M, Hazrati A, Esmaeili Gouvarchin Ghaleh H, Jonaidi-Jafari N, Abbaspour-Aghdam S, Malekpour K, Yousefi M, Samadi Kafil H, Jadidi-Niaragh F, Roshangar L, Valizadeh H, Izadi M, Ahmadi M. Exosomes from Adipose Tissue-derived Mesenchymal Stem Cells Induce Regulatory T Cells in COVID‐19 Patients. Iran J Allergy Asthma Immunol. 2023;22(3):233-244.
