Enhancing Mesenchymal Stromal Cell Immunomodulation for Treating Conditions Influenced by the Immune System

Abstract

Mesenchymal stromal cells (MSCs), formerly known as mesenchymal stem cells, are nonhematopoietic multipotent cells and are emerging worldwide as the most clinically used and promising source for allogeneic cell therapy. MSCs, initially obtained from bone marrow, can be derived from several other tissues, such as adipose tissue, placenta, and umbilical cord. Diversity in tissue sourcing and manufacturing procedures has significant effects on MSC products. However, in 2006, a minimal set of standard criteria has been issued by the International Society of Cellular Therapy for defining derived MSCs. These include adherence to plastic in conventional culture conditions, particular phenotype, and multilineage differentiation capacity in vitro. Moreover, MSCs have trophic capabilities, a high in vitro self-renewal ability, and immunomodulatory characteristics. Thus, immunosuppressive treatment with MSCs has been proposed as a potential therapeutic alternative for conditions in which the immune system cells influence outcomes, such as inflammatory and autoimmune diseases. The precise mechanism by which MSCs affect functions of most immune effector cells is not completely understood but involves direct contact with immune cells, soluble mediators, and local microenvironmental factors. Recently, it has been shown that their homeostatic resting state requires activation, which can be achieved in vitro with various cytokines, including interferon-γ. In the present review, we focus on the suppressive effect that MSCs exert on the immune system and highlight the significance of in vitro preconditioning and its use in preclinical studies. We discuss the clinical aspects of using MSCs as an immunomodulatory treatment. Finally, we comment on the risk of interfering with the immune system in regard to cancer formation and development.

Figure 1

Mechanisms mediating immunomodulation. MSCs and their derived extracellular vesicles (EVs) exert their effect on innate (NK, neutrophils, monocytes, and macrophages) and adaptive (B and T cells) immune systems, as well as dendritic cells (DCs) through cell-to-cell interactions and several immunomodulatory factors. Activated T cells activate resting MSCs, which in turn facilitate the recruitment of helper and effector T cells via CXCL9 and CXCL10. Several immunomodulatory factors (TGF-β, PGE2, and HLA-G5) and membrane-bound molecules (PD-L1) suppress CD4⁺ and CD8⁺ T cell proliferation and induce the polarization of CD4⁺ T cells towards Th17 cells. NO and IDO released by MSCs act on the suppression of CD8⁺ T cell proliferation, cytokine production, and cytotoxicity. MSCs support the development of Treg populations via IL-10, TGF-β, and HLA-G5. In the context of B cells, MSCs inhibit activation, proliferation, chemokine receptor expression, and differentiation to antibody-secreting plasma cells. MSCs suppress naïve macrophage polarization to proinflammatory M1 macrophage and then favor anti-inflammatory M2 polarization. IL-6 secreted by MSCs suppresses neutrophil apoptosis and respiratory burst.