Mesenchymal Stem Cell-Dependent Modulation of Liver Diseases

Abstract

Acute liver failure and cirrhosis display sequential and overlapping severe pathogenic processes that include inflammation, hepatocyte necrosis, and fibrosis, carrying a high mortality rate. Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells with immunonodulatory characteristics. MSCs are considered to act through multiple mechanisms to coordinate a dynamic, integrated response to liver inflammation and fibrosis, which prevents the progressive distortion of hepatic architecture. Accordingly, MSCs as well as their products have been investigated as a novel therapeutic approach for the treatment of inflammatory and fibrotic liver diseases. In this review, we highlight the current findings on the MSC-based modulation of liver inflammation and fibrosis, and the possible use of MSCs in the therapy of immune-mediated liver pathology. We briefly describe the cellular and molecular mechanisms involved in MSC-dependent modulation of cytokine production, phenotype and function of liver infiltrated inflammatory cells and compare effects of engrafted MSCs versus MSC-generated conditioned medium (MSC-CM) in the therapy of acute liver injury. In order to elucidate therapeutic potential of MSCs and their products in modulation of chronic liver inflammation and fibrosis, we present the current findings regarding pathogenic role of immune cells in liver fibrosis and describe mechanisms involved in MSC-dependent modulation of chronic liver inflammation with the brief overview of on-going and already published clinical trials that used MSCs for the treatment of immune mediated chronic liver diseases. The accumulating evidence shows that MSCs had a significant beneficial effect in the treatment of immune-mediated liver diseases.

Keywords: acute liver failure; cirrhosis; immune response; mesenchymal stem cells; therapy..

Figure 1

Therapeutic effects of MSCs in acute liver failure. MSCs isolated from different sources ameliorate acute liver injury by reducing the number of major effector cells in hepatic inflammation (CD4⁺ T lymphocytes, Gr-1⁺ neutrophils and CD11b⁺ F4/80⁺ macrophages). MSCs restrained acute liver injury through increasing production of protective IL-10 and by decreasing expression of TNF-α, IFN-γ, IL-4 and FasL in the CD4⁺lymphocytes and kupffer cells.

Figure 2

Potential protective mechanisms of MSCs in liver fibrosis. Immunomodulatory factors such as IL-10, HGF, NGF, TGF-β, and TNF-α secreted by MSCs inhibit proliferation and promote apoptosis of HSCs, leading to reduction in collagen and α-SMA synthesis. MSCs produce MMP-9 and MMP-13 resulting with increased degradation of ECM proteins. MSCs suppress liver fibrosis by attenuating infiltration of pro-fibrotic F4/80⁺ macrophages in the liver.