Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes

Abstract

Mesenchymal stem cells (MSCs) are pluripotent stromal cells that have the potential to give rise to cells of diverse lineages. Interestingly, MSCs can be found in virtually all postnatal tissues. The main criteria currently used to characterize and identify these cells are the capacity for self-renewal and differentiation into tissues of mesodermal origin, combined with a lack in expression of certain hematopoietic molecules. Because of their developmental plasticity, the notion of MSC-based therapeutic intervention has become an emerging strategy for the replacement of injured tissues. MSCs have also been noted to possess the ability to impart profound immunomodulatory effects in vivo. Indeed, some of the initial observations regarding MSC protection from tissue injury once thought mediated by tissue regeneration may, in reality, result from immunomodulation. Whereas the exact mechanisms underlying the immunomodulatory functions of MSC remain largely unknown, these cells have been exploited in a variety of clinical trials aimed at reducing the burden of immune-mediated disease. This article focuses on recent advances that have broadened our understanding of the immunomodulatory properties of MSC and provides insight as to their potential for clinical use as a cell-based therapy for immune-mediated disorders and, in particular, type 1 diabetes.

FIG. 1.

Schematic representation of plausible mechanisms by which MSCs regulate immune responses. MSCs might also reduce the generation and differentiation of dendritic cells (1). MSCs can increase the percentage of regulatory T-cells through production of cytokines imparting regulation or promoting the generation of regulatory dendritic cells producing IL-10 (2). MSCs may engage in cell-to-cell contact through a variety of receptors with T-cells and endothelial cells (3,4). In addition, MSCs could suppress effector T-cells through various growth factors, inducible nitric oxide synthase (iNOS), heme oxygenase (HO)-1, prostaglandin (PG), or indolamine 2,3-dioxygenase (IDO) (5). MSCs may also act through downregulation of immunoglobulin production by B-cells (6). Finally, upregulation of MHC class II on MSCs could lead to downregulation of NK cell cytotoxity and proliferation (7). DC, dendritic cells; HGF, hepatic growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor.