Secretion of immunoregulatory cytokines by mesenchymal stem cells

Abstract

According to the minimal criteria of the International Society of Cellular Therapy, mesenchymal stem cells (MSCs) are a population of undifferentiated cells defined by their ability to adhere to plastic surfaces when cultured under standard conditions, express a certain panel of phenotypic markers and can differentiate into osteogenic, chondrogenic and adipogenic lineages when cultured in specific inducing media. In parallel with their major role as undifferentiated cell reserves, MSCs have immunomodulatory functions which are exerted by direct cell-to-cell contacts, secretion of cytokines and/or by a combination of both mechanisms. There are no convincing data about a principal difference in the profile of cytokines secreted by MSCs isolated from different tissue sources, although some papers report some quantitative but not qualitative differences in cytokine secretion. The present review focuses on the basic cytokines secreted by MSCs as described in the literature by which the MSCs exert immunodulatory effects. It should be pointed out that MSCs themselves are objects of cytokine regulation. Hypothetical mechanisms by which the MSCs exert their immunoregulatory effects are also discussed in this review. These mechanisms may either influence the target immune cells directly or indirectly by affecting the activities of predominantly dendritic cells. Chemokines are also discussed as participants in this process by recruiting cells of the immune systems and thus making them targets of immunosuppression. This review aims to present and discuss the published data and the personal experience of the authors regarding cytokines secreted by MSCs and their effects on the cells of the immune system.

Keywords: Chemokines; Cytokines; Dendritic cells; Immunomodulation; Mesenchymal stem cells.

Figure 1

Effect of Interleukin 6 on Th17 formation. IL-6 exerts a dual effect on the generation of Th17 cells. On one side, IL-6 in concert with TGFβ facilitates the generation of this cell population and on the other side, IL-6 inhibits the Th17 cells by inducing the generation of CD8⁺FoxP3⁺ T lymphocytes. TGFβ: Transforming growth factor β.

Figure 2

Mesenchymal stem cells provide an immunoregulatory effect by interactions with dendritic cells and T regulatory cells. Under the influence of cytokines secreted by MSCs and autocrine secreted interleukin-10 (IL-10), the dendritic cells acquire an immature tolerogenic phenotype characterized by a low expression of MHC II and B7 molecules, as well as a higher secretion of IL-10. The secretion of IL-10 induces generation of different subtypes of regulatory T cells which further secrete IL-10 and induce tolerogenic phenotype in dendritic cells. Cytokines secreted from MSCs also lead directly to formation of regulatory T cells. VEGF: Vascular endothelial growth factor; PGE2: Prostaglandin E2; MSCs: Mesenchymal stem cells; IDO: Indoleamine-2, 3-dioxygenase; TGFβ: Transforming growth factor β; DCs: Dendritic cells; IL: Interleukin; CCL: CC chemokine ligand.