Mesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic Potential

Abstract

Mesenchymal stem/stromal cells (MSCs) are multipotent cells that are emerging as the most promising means of allogeneic cell therapy. MSCs have inherent immunomodulatory characteristics, trophic activity, high invitro self-renewal ability, and can be readily engineered to enhance their immunomodulatory functions. MSCs affect the functions of most immune effector cells via direct contact with immune cells and local microenvironmental factors. Previous studies have confirmed that the immunomodulatory effects of MSCs are mainly communicated via MSC-secreted cytokines; however, apoptotic and metabolically inactivated MSCs have more recently been shown to possess immunomodulatory potential, in which regulatory T cells and monocytes play a key role. We review the immunomodulatory aspects of naïve and engineered MSCs, and discuss strategies for increasing the potential of successfully using MSCs in clinical settings.

Keywords: engineering; immunomodulation; mesenchymal stem cells; therapeutics.

Figure 1.. Multi-faceted immunomodulatory interactions between MSCs and immune cells.

MSCs exert immunomodulatory functions mainly via interactions with immune cells such as T cells, B cells, natural killer (NK) cells, macrophages, monocytes, dendritic cells (DCs) and neutrophils, through cell-to-cell contacts (blue arrows) and paracrine activity (shown by secretome). MSCs’ secretome bear a number of cytokines, growth factors, and chemokines and the immunomodulatory functions vary depending on the sources of the MSCs, target cells, and the microenvironment. Abbreviations: ICAM-1, intercellular adhesion molecule-1; IDO, indoleamine-pyrrole 2,3-dioxygenase; IFN, interferon; IL, interleukin; PD-L1, programmed-death ligand 1; PD-L2, programmed-death ligand 2; PGE2, prostaglandin E2; TGF- β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Figure 2.. Three strategies to enhance the efficacy of MSC application

(A) MSCs can be engineered with immunomodulatory molecules like interferons (IFNs), interleukins (ILs) and miRNA or engineered to deliver oncolytic viruses. (B) MSCs can also be primed which can contribute to their efficient homing and migration to the target tissue. (C) Different methods have been modified and standardized to improve the cryopreservation of MSC. Abbreviations: CSF-2, Colony-stimulating factor 2; CXCR4, CXC chemokine receptor 4; IFN, interferon; IL, interleukin; IGFBP3, insulin-like growth factor binding protein 3; miRNA, microRNA, SDF-1, stromal cell-derived factor-1.