Abstract
Liver transplantation is the treatment of choice for chronic liver failure, although it is complicated by donor shortage, surgery-related complications, and immunological rejection. Cell transplantation is an alternative, minimally invasive treatment option with potentially fewer complications. We used human palatine tonsil as a novel source of mesenchymal stem cells (T-MSCs) and examined their ability to differentiate into hepatocyte-like cells in vivo and in vitro. Carbon tetrachloride (CCl4) mouse model was used to investigate the ability of T-MSCs to home to the site of liver injury. T-MSCs were only detected in the damaged liver, suggesting that they are disease-responsive. Differentiation of T-MSCs into hepatocyte-like cells was confirmed in vitro as determined by expression of hepatocyte markers. Next, we showed resolution of liver fibrosis by T-MSCs via reduction of TGF-β expression and collagen deposition in the liver. We hypothesized that autophagy activation was a possible mechanism for T-MSC-mediated liver recovery. In this report, we demonstrate for the first time that T-MSCs can differentiate into hepatocyte-like cells and ameliorate liver fibrosis via autophagy activation and down-regulation of TGF-β. These findings suggest that T-MSCs could be used as a novel source for stem cell therapy targeting liver diseases.
Highlights
Liver transplantation is the treatment of choice for chronic liver failure, it is complicated by donor shortage, surgery-related complications, and immunological rejection
We demonstrate for the first time that T-Mesenchymal stem cells (MSCs) can differentiate into hepatocyte-like cells and ameliorate liver fibrosis via autophagy activation and down-regulation of transforming growth factor-b (TGF-b)
We investigated the potential of T-MSCs to differentiate into cells of mesodermal origin by culturing them in differentiation culture medium for 3 weeks
Summary
There was an increase in the numbers of albumin and HNF-4a positive cells at 7 days post-infusion, which suggested that T-MSCs recruited into the CCl4-injured liver differentiated into hepatocyte-like cells. To confirm this possibility in vitro, we cultured T-MSCs in differentiation medium containing insulin-like growth factor (IGF), hepatocyte growth factor (HGF), dexamethasone, and oncostatin M (OSM) to induce the commitment of T-MSCs to the hepatic lineage. We stained liver tissue for the detection of LC3, beclin-1, and ubiquitin, showing that these autophagy-related proteins were expressed in T-MSCs and parenchymal cells from the CCl4-injured mice (Figure 5A). Autophagy inhibition again neutralized the effect of T-MSCs (Figure 5C)
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