Individual Immune-Modulatory Capabilities of MSC-Derived Extracellular Vesicle (EV) Preparations and Recipient-Dependent Responsiveness

Int J Mol Sci. 2019 Apr 2;20(7):1642. doi: 10.3390/ijms20071642.


Treatment with extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have been suggested as novel therapeutic option in acute inflammation-associated disorders due to their immune-modulatory capacities. As we have previously observed differences in the cytokine profile of independent MSC-EV preparations, functional differences of MSC-EV preparations have to be considered. To evaluate the immune-modulatory capabilities of specific MSC-EV preparations, reliable assays are required to characterize the functionality of MSC-EV preparations prior to administration to a patient. To this end, we established an in vitro assay evaluating the immune-modulatory capacities of MSC-EV preparations. Here, we compared the efficacy of four independent MSC-EV preparations to modulate the induction of T cell differentiation and cytokine production after phorbol 12-myristate 13-acetate (PMA)/Ionomycin stimulation of peripheral blood mononuclear cells (PBMC) derived from six healthy donors. Flow cytometric analyses revealed that the four MSC-EV preparations differentially modulate the expression of surface markers, such as CD45RA, on CD4+ and CD8+ T cells, resulting in shifts in the frequencies of effector and effector memory T cells. Moreover, cytokine profile in T cell subsets was affected in a MSC-EV-specific manner exclusively in CD8+ naïve T cells. Strikingly, hierarchical clustering revealed that the T cell response towards the MSC-EV preparations largely varied among the different PBMC donors. Thus, besides defining functional activity of MSC-EV preparations, it will be crucial to test whether patients intended for treatment with MSC-EV preparations are in principal competent to respond to the envisioned MSC-EV therapy.

Keywords: Graft-versus-Host-Disease (GvHD); extracellular vesicles (EV); mesenchymal stem/stromal cells (MSC).

MeSH terms

  • Cell Differentiation / drug effects
  • Cluster Analysis
  • Cytokines / biosynthesis
  • Extracellular Vesicles / drug effects
  • Extracellular Vesicles / metabolism*
  • Humans
  • Immunomodulation* / drug effects
  • Ionomycin / pharmacology
  • Leukocyte Common Antigens / metabolism
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology


  • Cytokines
  • Ionomycin
  • Leukocyte Common Antigens
  • Tetradecanoylphorbol Acetate