Liver Disease: Induction, Progression, Immunological Mechanisms, and Therapeutic Interventions

Abstract

The liver is an organ with impressive regenerative potential and has been shown to heal sizable portions after their removal. However, certain diseases can overstimulate its potential to self-heal and cause excessive cellular matrix and collagen buildup. Decompensation of liver fibrosis leads to cirrhosis, a buildup of fibrotic ECM that impedes the liver's ability to efficiently exchange fluid. This review summarizes the complex immunological activities in different liver diseases, and how failure to maintain liver homeostasis leads to progressive fibrotic tissue development. We also discuss a variety of pathologies that lead to liver cirrhosis, such as alcoholic liver disease and chronic hepatitis B virus (HBV). Mesenchymal stem cells are widely studied for their potential in tissue replacement and engineering. Herein, we discuss the potential of MSCs to regulate immune response and alter the disease state. Substantial efforts have been performed in preclinical animal testing, showing promising results following inhibition of host immunity. Finally, we outline the current state of clinical trials with mesenchymal stem cells and other cellular and non-cellular therapies as they relate to the detection and treatment of liver cirrhosis.

Keywords: alcoholic liver disease; apoptosis; autoimmune disease; cirrhosis; clinical trials; cytokines; fibrosis; hepatitis; hepatocyte; immunomodulation; in vivo; liver; mesenchymal stem cells; non-alcoholic fatty liver disease.

Figure 1

Original schematic depicting the immunological mechanism behind liver fibrosis, cirrhosis, and failure. A summary schematic of hepatic stellate cell (HpSC)-initiated extracellular matrxi (ECM) deposition, where imbalanced tissue inhibitors of metalloproteinase (TIMP)/matrix metalloproteinase (MMP) ratios lead to less proteolytic activity and increased collagen synthesis. HBV: hepatitis B virus, HCV: hepatitis C virus, DAMP: damage-associated molecular pattern, PAMP: pathogen-associated molecular pattern, NK: natural killer, TGF-β: transforming growth factor β, TNFα: tumor necrosis factor-alpha, ROS: reactive oxygen species, IL: interleukin, EGF: epidermal growth factor, VEGF: vascular endothelial growth factor, NF-κB: nuclear factor-kappa B, CXCL: chemokine (C-X-C motif) ligand. Original schematic was created with BioRender.com.

Figure 2

Expression of select fibrotic factors via immunohistochemistry. (A–C). TGF-β1 (A), collagen type 1 (B) and α-smooth muscle actin (C) expression at 1, 2, and 4 weeks. It can be visually determined that the fibrotic effect is reduced with treatment of human umbilical cord blood-derived mesenchymal stem cells (hMSCs) as opposed to CCl4 induced cirrhosis and saline. Mice livers injected with saline (left), olive oil and hMSC injection (left center), CCl4 induced cirrhosis with saline injection (right center) and CCl4 induced cirrhosis with hMSC injection (right) on each of the three panels. The MSC injection group shows a 4-fold decrease in αSMA and TGF-β and a 3-fold decrease in collagen 1 at 4 weeks with n = 5 mice. The study demonstrates MSC homing into the cirrhotic livers more so compared to healthy livers, further signifying the efficacy of the cellular therapy. Original magnification of 200×. Values are presented as mean ± SEM, for at least five separate experiments. Data are presented as fold change with respect to saline/CCl4 group, * p < 0.05, ** p < 0.01. Reprinted with permissions from Jung et al. [79].

Figure 3

Transplanted microencapsulated mesenchymal stem cells can be used to aid liver fibrosis. (A–D) MSCs were encapsulated in novel alginate-polyethylene glycol microspheres and transplanted into BDL or CCl4-induced mice, then livers were harvested after 15 days or 4 weeks, respectively. (A,C) Morphometric quantification of Masson’s trichrome stained sections was calculated, showing a decrease in fibrotic surface area with encapsulated MSC treatment. Scale bars are 400 μm. (E–L) Real time-PCR analysis was conducted for Col1a, α-SMa, MMP-9, and MMP-13 gene markers. The results reveal reduced expression of collagen type 1 in with encapsulated MSC treatment compared to untreated. Increase in α-SMa, MMP-9, and MMP-13 gene expression was observed in both BDL and CCl4-induced models when treated with encapsulated MSCs compared to encapsulated foreskin fibroblasts. MMP-9 is known to be overexpressed in cell population such as neutrophils and lymphocytes, which can curb accumulation of extracellular matrix and thus reduce liver fibrosis pathology. Data presented as fold change with respect to housekeeping genes and expressed as mean value ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001. Reprinted with permissions from Meier et al. [78].