Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

Ahead of print

doi: 10.17219/acem/156643

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Cite as:


Sang H, Zhao R, Lai G, et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate the maturation of dendritic cells and reduce the rejection of allogeneic transplantation [published online as ahead of print on March 7, 2023]. Adv Clin Exp Med. 2023. doi:10.17219/acem/156643

Bone marrow mesenchymal stem cell-derived exosomes attenuate the maturation of dendritic cells and reduce the rejection of allogeneic transplantation

Hongxun Sang1,A, Renli Zhao2,B, Guohua Lai2,3,B,C, Zhiwei Deng4,B,C, Weida Zhuang1,C,E, Mingjie Wu3,C,E, Jiachang Wu1,A,E

1 Department of Orthopedic Surgery, Shenzhen Hospital of Southern Medical University, China

2 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China

4 Division of Spine Surgery, Section II, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Southern Medical University, Academy of Orthopedics of Guangdong Province, Guangzhou, China

Abstract

Background. Bone mesenchymal stem cell (BMSC)-derived exosomes (B-exos) are attractive for applications in enabling alloantigen tolerance. An in-depth mechanistic understanding of the interaction between B-exos and dendritic cells (DCs) could lead to novel cell-based therapies for allogeneic transplantation.
Objectives. To examine whether B-exos exert immunomodulatory effects on DC function and maturation.
Material and Methods. After mixed culture of BMSCs and DCs for 48 h, DCs from the upper layer were collected to analyze the expression levels of surface markers and mRNAs of inflammation-related cytokines. Then, before being collected to detect the mRNA and protein expression levels of indoleamine 2,3-dioxygenase (IDO), the DCs were co-cultured with B-exos. Then, the treated DCs from different groups were co-cultured with naïve CD4+ T cells from the mouse spleen. The proliferation of CD4+ T cells and the proportion of CD4+CD25+Foxp3+ T cells were analyzed. Finally, the skins of BALB/c mice were transplanted to the back of C57 mice in order to establish a mouse allogeneic skin transplantation model.
Results. The co-culture of DCs with BMSCs downregulated the expression of the major histocompatibility complex class II (MHC-II) and CD80/86 costimulatory molecules on DCs. Moreover, B-exos increased the expression of IDO in DCs treated with lipopolysaccharide (LPS). The proliferation of CD4+CD25+Foxp3+ T cells increased when cultured with B-exos-exposed DCs. Finally, mice recipients injected with B-exos-treated DCs had significantly prolonged survival after receiving the skin allograft.
Conclusion. Taken together, these data suggest that the B-exos suppress the maturation of DCs and increase the expression of IDO, which might shed light on the role of B-exos in inducing alloantigen tolerance.

Key words

exosomes, tolerance, bone marrow mesenchymal stem cell

Graphical abstract


Graphical abstracts

References (32)

  1. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–147. doi:10.1126/science.284.5411.143
  2. Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy. 2003;5(6):485–489. doi:10.1080/14653240310003611
  3. Li X, Dong Y, Yin H, Qi Z, Wang D, Ren S. Mesenchymal stem cells induced regulatory dendritic cells from hemopoietic progenitor cells through Notch pathway and TGF-β synergistically. Immunol Lett. 2020;222:49–57. doi:10.1016/j.imlet.2020.03.005
  4. Palomares Cabeza V, Hoogduijn MJ, Kraaijeveld R, et al. Pediatric mesenchymal stem cells exhibit immunomodulatory properties toward allogeneic T and B cells under inflammatory conditions. Front Bioeng Biotechnol. 2019;7:142. doi:10.3389/fbioe.2019.00142
  5. Li YP, Paczesny S, Lauret E, et al. Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway. J Immunol. 2008;180(3):1598–1608. doi:10.4049/jimmunol.180.3.1598
  6. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem. 1998;273(32):20121–20127. doi:10.1074/jbc.273.32.20121
  7. Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–383. doi:10.1083/jcb.201211138
  8. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–252. doi:10.1038/32588
  9. Lanzavecchia A, Sallusto F. Regulation of T cell immunity by dendritic cells. Cell. 2001;106(3):263–266. doi:10.1016/S0092-8674(01)00455-X
  10. Yoo S, Ha SJ. Generation of tolerogenic dendritic cells and their therapeutic applications. Immune Netw. 2016;16(1):52–60. doi:10.4110/in.2016.16.1.52
  11. Shahir M, Mahmoud Hashemi S, Asadirad A, et al. Effect of mesenchymal stem cell-derived exosomes on the induction of mouse tolerogenic dendritic cells. J Cell Physiol. 2020;235(10):7043–7055. doi:10.1002/jcp.29601
  12. Soleimani M, Nadri S. A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc. 2009;4(1):102–106. doi:10.1038/nprot.2008.221
  13. Kowal J, Arras G, Colombo M, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113(8):E968–E977. doi:10.1073/pnas.1521230113
  14. Wang W, Li J, Wu K, Azhati B, Rexiati M. Culture and identification of mouse bone marrow-derived dendritic cells and their capability to induce T lymphocyte proliferation. Med Sci Monit. 2016;22:244–250. doi:10.12659/MSM.896951
  15. Xiao C, Wang K, Xu Y, et al. Transplanted mesenchymal stem cells reduce autophagic flux in infarcted hearts via the exosomal transfer of miR-125b. Circ Res. 2018;123(5):564–578. doi:10.1161/CIRCRESAHA.118.312758
  16. Jain A, Irizarry-Caro RA, McDaniel MM, et al. T cells instruct myeloid cells to produce inflammasome-independent IL-1β and cause autoimmunity. Nat Immunol. 2020;21(1):65–74. doi:10.1038/s41590-019-0559-y
  17. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25(4):402–408. doi:10.1006/meth.2001.1262
  18. Cheng C, Lee C, Fryer M, et al. Murine full thickness skin transplantation. J Vis Exp. 2017;119:55105. doi:10.3791/55105
  19. Zheng Q, Zhang S, Guo WZ, Li XK. The unique immunomodulatory properties of MSC-derived exosomes in organ transplantation. Front Immunol. 2021;12:659621. doi:10.3389/fimmu.2021.659621
  20. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther. 2016;7(1):125. doi:10.1186/s13287-016-0363-7
  21. Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018;156:16–27. doi:10.1016/j.biomaterials.2017.11.028
  22. Askenase PW. COVID-19 therapy with mesenchymal stromal cells (MSC) and convalescent plasma must consider exosome involvement: Do the exosomes in convalescent plasma antagonize the weak immune antibodies? J Extracell Vesicles. 2020;10(1):e12004. doi:10.1002/jev2.12004
  23. Castenmiller C, Keumatio-Doungtsop BC, van Ree R, de Jong EC, van Kooyk Y. Tolerogenic immunotherapy: Targeting DC surface receptors to induce antigen-specific tolerance. Front Immunol. 2021;12:643240. doi:10.3389/fimmu.2021.643240
  24. Obregon C, Kumar R, Pascual MA, Vassalli G, Golshayan D. Update on dendritic cell-induced immunological and clinical tolerance. Front Immunol. 2017;8:1514. doi:10.3389/fimmu.2017.01514
  25. ten Brinke A, Martinez-Llordella M, Cools N, et al. Ways forward for tolerance-inducing cellular therapies: An AFACTT perspective. Front Immunol. 2019;10:181. doi:10.3389/fimmu.2019.00181
  26. Mellor AL, Lemos H, Huang L. Indoleamine 2,3-dioxygenase and tolerance: Where are we now? Front Immunol. 2017;8:1360. doi:10.3389/fimmu.2017.01360
  27. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008;181(8):5396–5404. doi:10.4049/jimmunol.181.8.5396
  28. Chung DJ, Rossi M, Romano E, et al. Indoleamine 2,3-dioxygenase–expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood. 2009;114(3):555–563. doi:10.1182/blood-2008-11-191197
  29. Zhang B, Yin Y, Lai RC, Tan SS, Choo ABH, Lim SK. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014;23(11):1233–1244. doi:10.1089/scd.2013.0479
  30. Thomson AW, Humar A, Lakkis FG, Metes DM. Regulatory dendritic cells for promotion of liver transplant operational tolerance: Rationale for a clinical trial and accompanying mechanistic studies. Hum Immunol. 2018;79(5):314–321. doi:10.1016/j.humimm.2017.10.017
  31. Li D, Zhao B, Luo Y, et al. Transplantation of Aire-overexpressing bone marrow-derived dendritic cells delays the onset of type 1 diabetes. Int Immunopharmacol. 2017;49:13–20. doi:10.1016/j.intimp.2017.05.023
  32. Monguió-Tortajada, M, Lauzurica-Valdemoros R, Borràs FE. Tolerance in organ transplantation: From conventional immunosuppression to extracellular vesicles. Front Immunol. 2014;5:416. doi:10.3389/fimmu.2014.00416
© Wroclaw Medical University