Immunomodulatory properties of exosomes

Extracellular vesicles (EVs) offer a new approach for treatment of diseases and immunotherapy. EVs have already demonstrated their immunomodulatory properties: in the treatment of sepsis¹, EVs lowered the level of inflammatory mediators. In the treatment of GVHD², EVs reduced the level TNF-a, IL-2 and IFN-y. Finally in auto-immune diseases³, EVs inhibited the migration of inflammatory cells and reduced the level of inflammatory mediators. In clinical studies, EVs have shown their immunomodulatory properties in the treatment of COVID-19 by downregulating the cytokine storm⁴, but also in chronic kidney disease (CKD) where a significant increase in anti-inflammatory mediators and an improvement of kidney function was observed⁵. Though, depending on the cell of origin, EVs can exert immunostimulatory or immunosuppressive activities.⁶ As an example, EVs from macrophages infected with mycobacterium contained pro-inflammatory molecules, inducing the secretion of pro-inflammatory cytokines.⁷ EVs derived from tumor cells have immunosuppressive activities, allowing cells to escape the immune system.⁸ EVs secreted by dendritic cells can express major histocompability complex (MHC) and co-stimulatory molecules, triggering anti-tumor responses.⁹

Immunomodulatory properties of MSCs are partially mediated by secreted EVs. Thus, the action of EVs from stem cells is mainly described as immunosuppressive and regulatory, with direct effects on various immune cells through diverse factors such as PD-1, TGF- β, PGE2 or IDO. These effects have been described on the transplantation of islets of Langerhans¹⁰, the polarization of macrophages into M2 anti-inflammatory in a rat model of vascular graft, or through the regulation of anti-inflammatory and inflammatory cytokines in a model of neuronal regeneration.¹¹ Nonetheless, the characterization of MSC’s secretome shows the simultaneous presence of pro and anti-inflammatory proteins. ^12–14

The immunomodulatory action of MSC derived EVs can vary depending on many factors. The cell source, even between different MSCs of adipose tissue, umbilical cord or bone marrow¹⁵, the state of the cell and passage¹⁶, the production method¹⁶,  and the downstream process such as isolation, concentration, and EV purification are many existing factors which can impact the immunomodulatory activity of EVs. Notably, some production methods can increase the immunomodulatory activity, such as hypoxia¹⁷ or cell priming.^18,19

Despite all these differences, data indicate that EVs derived from MSCs has potential for the treatment of immunological diseases. Nevertheless, in order to develop a successful and effective immunotherapy, more studies are needed to clarify the mechanism of action of EVs and standardization of isolation and characterization of EVs.²⁰

 1.           Chang, C.-L. et al. Adipose-derived mesenchymal stem cell-derived exosomes alleviate overwhelming systemic inflammatory reaction and organ damage and improve outcome in rat sepsis syndrome. Am. J. Transl. Res. 10, 1053–1070 (2018).

2.            Lai, P. et al. A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD. J. Hematol. Oncol.J Hematol Oncol 11, 135 (2018).

3.            Bai, L. et al. Effects of Mesenchymal Stem Cell-Derived Exosomes on Experimental Autoimmune Uveitis. Sci. Rep. 7, 4323 (2017).

4.            Sengupta, V. et al. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells Dev. 29, 747–754 (2020).

5.            Nassar, W. et al. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater. Res. 20, 21 (2016).

6.            Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).

7.            Bhatnagar, S. & Schorey, J. S. Exosomes Released from Infected Macrophages Contain Mycobacterium avium Glycopeptidolipids and Are Proinflammatory*. J. Biol. Chem. 282, 25779–25789 (2007).

8.            Clayton, A., Mitchell, J. P., Court, J., Mason, M. D. & Tabi, Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 67, 7458–7466 (2007).

9.            Fernández-Delgado, I., Calzada-Fraile, D. & Sánchez-Madrid, F. Immune Regulation by Dendritic Cell Extracellular Vesicles in Cancer Immunotherapy and Vaccines. Cancers 12, 3558 (2020).

10.           Shrestha, M. et al. Immunomodulation effect of mesenchymal stem cells in islet transplantation. Biomed. Pharmacother. 142, 112042 (2021).

11.           Ma, Y. et al. Extracellular vesicles from human umbilical cord mesenchymal stem cells improve nerve regeneration after sciatic nerve transection in rats. J. Cell. Mol. Med. 23, 2822–2835 (2019).

12.           Islam, A., Urbarova, I., Bruun, J. A. & Martinez-Zubiaurre, I. Large-scale secretome analyses unveil the superior immunosuppressive phenotype of umbilical cord stromal cells as compared to other adult mesenchymal stromal cells. Eur. Cell. Mater. 37, 153–174 (2019).

13.           Brandhorst, H. et al. Proteomic Profiling Reveals the Ambivalent Character of the Mesenchymal Stem Cell Secretome: Assessing the Effect of Preconditioned Media on Isolated Human Islets. Cell Transplant. 29, 096368972095233 (2020).

14.           Kiselevskii, M. V. et al. Secretome of Mesenchymal Bone Marrow Stem Cells: Is It Immunosuppressive or Proinflammatory? Bull. Exp. Biol. Med. 172, 250–253 (2021).

15.           Tang, Y., Zhou, Y. & Li, H.-J. Advances in mesenchymal stem cell exosomes: a review. Stem Cell Res. Ther. 12, 71 (2021).

16.           Kim, H. et al. Comprehensive Molecular Profiles of Functionally Effective MSC-Derived Extracellular Vesicles in Immunomodulation. Mol. Ther. 28, 1628–1644 (2020).

17.           Gómez-Ferrer, M. et al. HIF-1α and Pro-Inflammatory Signaling Improves the Immunomodulatory Activity of MSC-Derived Extracellular Vesicles. Int. J. Mol. Sci. 22, 3416 (2021).

18.           Kim, D. S. et al. Enhanced Immunosuppressive Properties of Human Mesenchymal Stem Cells Primed by Interferon-γ. EBioMedicine 28, 261–273 (2018).

19.           Yang, R. et al. IFN-γ promoted exosomes from mesenchymal stem cells to attenuate colitis via miR-125a and miR-125b. Cell Death Dis. 11, 1–12 (2020).

20.          Théry, C. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750 (2018).