Implications of the immunoregulatory functions of mesenchymal stem cells in the treatment of human liver diseases

Abstract

Transplantation of mesenchymal stem cells (MSCs) has been recently studied in animal models, and in clinical trials of patients with fulminant hepatic failure, end-stage liver diseases and inherited metabolic disorders. Modulatory cytokines produced by MSCs can inhibit immunocyte proliferation and migration to the liver, thereby attenuating inflammatory injury and reducing hepatocyte apoptosis. In addition, MSCs play an important role in regressing liver fibrosis and in supporting the function, proliferation and differentiation of endogenous hepatocytes under appropriate conditions. Although remarkable progress has been achieved in basic and clinical MSC studies, optimal therapeutic regimens for the clinical application of MSCs, such as optimal doses, transplantation routine and interval period for transplantation, need to be elucidated in detail. Furthermore, the long-term safety and therapeutic efficacy of MSC transplantation should be evaluated in future clinical trials. This review summarizes our current understanding of the immunomodulatory effects of MSC therapies on human liver diseases.

Figure 1

Trophic mechanisms of MSC therapy. Mediator-specific effects of MSC-derived factors on pathophysiological processes in liver injury. EGF, epidermal growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor-1; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; MMP, matrix metalloproteinase; MSC, mesenchymal stem cell; LRP, liver-regulating protein; TGF-β, transforming growth factor-β SCF, stem cell factor; SDF-1, stromal cell-derived factor-1; TNF-α, tumor necrosis factor-α VEGF, vascular endothelial growth factor.

Figure 2

Immunomodulatory properties of MSCs. MSCs modulate the functions of the immune system by interacting with a wide range of immune cells, including T lymphocytes, B lymphocytes, natural killer cells and dendritic cells, by secreting dissoluble cytokines and by direct cell–cell contacts. MSCs inhibit T-cell proliferation in a dose-dependent manner: the greater the number of MSCs, the greater the inhibition of T-cell proliferation. In contrast, the greater the number of MSCs, the lower the inhibition of B-cell proliferation. HGF, hepatocyte growth factor; IDO, indoleamine 2,3-dioxygenase; IL-6, interleukin-6; MCSF, macrophage colony-stimulating factor; MSCs, mesenchymal stem cells; PGE2, prostaglandin E2; TGF-β, transforming growth factor-β.