Extrinsic and Intrinsic Mechanisms by Which Mesenchymal Stem Cells Suppress the Immune System

Abstract

Mesenchymal stem cells (MSCs) are a group of fibroblast-like multipotent mesenchymal stromal cells that have the ability to differentiate into osteoblasts, adipocytes, and chondrocytes. Recent studies have demonstrated that MSCs possess a unique ability to exert suppressive and regulatory effects on both adaptive and innate immunity in an autologous and allogeneic manner. A vital step in stem cell transplantation is overcoming the potential graft-versus-host disease, which is a limiting factor to transplantation success. Given that MSCs attain powerful differentiation capabilities and also present immunosuppressive properties, which enable them to survive host immune rejection, MSCs are of great interest. Due to their ability to differentiate into different cell types and to suppress and modulate the immune system, MSCs are being developed for treating a plethora of diseases, including immune disorders. Moreover, in recent years, MSCs have been genetically engineered to treat and sometimes even cure some diseases, and the use of MSCs for cell therapy presents new perspectives for overcoming tissue rejection. In this review, we discuss the potential extrinsic and intrinsic mechanisms that underlie MSCs' unique ability to modulate inflammation, and both innate and adaptive immunity.

Keywords: graft versus host disease; immunity; inflammation; mesenchymal stem cells; stem cell transplantation.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Figure 1

Schematic of the intrinsic mechanisms by which MSCs modulate the inflammatory response. MSCs respond differently to pro-inflammatory and anti-inflammatory environments. In an anti-inflammatory environment (low levels of IFN-γ) TLR4 activation in MSCs leads to MHC-II expression and the presentation of antigens to T cells, which in turn secrete IFN-γ creating a pro-inflammatory environment. In a pro-inflammatory environment TLR3 activation leads to the secretion of anti-inflammatory cytokines such as IL-10, TGF-β, Sema3A and galectin-1 and -3 thereby creating an anti-inflammatory environment and inhibiting T-cell, neutrophil and macrophage (Mφ) recruitment. Thus, the delicate balance of IFN-γ in the MSC environment dictates MSC phenotype

Figure 2

Schematic of the extrinsic mechanisms by which MSCs modulate the inflammatory response. MSCs express a rich glycocalyx composed of HA/HCs/TSG-6/PTX3 which actively suppresses inflammatory cells. A soluble form of HA/HCs/TSG-6/PTX3 inhibits maturation of M1 macrophages and promotes the maturation of M2 macrophages. The HA cables produced sequester macrophages maintaining them in a non-polarized state (M0).

Figure 3

UMSCs in vitro and in vivo. (A) UMSCs in culture prior to transplantation into mouse corneal stroma. (B) 1 month after transplantation UMSCs assume keratocyte-like morphology and express a keratocyte cell marker in the corneal stroma.

Figure 4

Schematic of MSC therapeutic developments for treating inflammatory disorders of the ocular surface. Various clinical applications have been developed for treating inflammatory disorders associated with the corneal epithelium (listed below the image) and stroma (listed above the image). However MSC treatments for curing endothelial defects remain to be developed. Each line represents a study with the type of MSC used listed in bold, followed by the condition being treated and finally the mechanism by which the MSCs resolve the condition listed in parenthesis.