Abstract
BackgroundHuman amniotic membrane-derived mesenchymal stem cells (hAMCs) have the potential to reduce heart and lung fibrosis, but whether could reduce liver fibrosis remains largely unknown.Methodology/Principal FindingsHepatic cirrhosis model was established by infusion of CCl4 (1 ml/kg body weight twice a week for 8 weeks) in immunocompetent C57Bl/6J mice. hAMCs, isolated from term delivered placenta, were infused into the spleen at 4 weeks after mice were challenged with CCl4. Control mice received only saline infusion. Animals were sacrificed at 4 weeks post-transplantation. Blood analysis was performed to evaluate alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Histological analysis of the livers for fibrosis, hepatic stellate cells activation, hepatocyte apoptosis, proliferation and senescence were performed. The donor cell engraftment was assessed using immunofluorescence and polymerase chain reaction. The areas of hepatic fibrosis were reduced (6.2%±2.1 vs. control 9.6%±1.7, p<0.05) and liver function parameters (ALT 539.6±545.1 U/dl, AST 589.7±342.8 U/dl,vs. control ALT 139.1±138.3 U/dl, p<0.05 and AST 212.3±110.7 U/dl, p<0.01) were markedly ameliorated in the hAMCs group compared to control group. The transplantation of hAMCs into liver-fibrotic mice suppressed activation of hepatic stellate cells, decreased hepatocyte apoptosis and promoted liver regeneration. More interesting, hepatocyte senescence was depressed significantly in hAMCs group compared to control group. Immunofluorescence and polymerase chain reaction revealed that hAMCs engraftment into host livers and expressed the hepatocyte-specific markers, human albumin and α-fetoproteinran.Conclusions/SignificanceThe transplantation of hAMCs significantly decreased the fibrosis formation and progression of CCl4-induced cirrhosis, providing a new approach for the treatment of fibrotic liver disease.
Highlights
Liver cirrhosis is a common end-stage of a wide variety of chronic hepatic diseases caused by a variety of factors, such as viral infections, alcohol, drugs and chemical toxicity [1,2,3,4]
After 8 weeks of CCl4 challenge, desmin, alphasmooth muscle actin (a-SMA)- and GFAPpositive hepatic stellate cells (HSC) were strongly and diffusely present near the expanding septa and in the perisinusoidal spaces of sidual hepatic parenchyma. Human amniotic membrane-derived mesenchymal stem cells (hAMCs) transplantation significantly reduced the percentages of these positive HSCs [desmin 35.2%65.8, a-SMA 52.3%611.2, glial fibrillary acidic protein (GFAP) 51.7%612.2 in control group vs. desmin 17.2%63.8, a-SMA 22.3%68.5, GFAP 21.1%69.2 in hAMCs group, p,0.05, Fig. 3]
The aim of this study was to evaluate the effect of hAMCs transplantation for the improvement of hepatic fibrosis
Summary
Liver cirrhosis is a common end-stage of a wide variety of chronic hepatic diseases caused by a variety of factors, such as viral infections, alcohol, drugs and chemical toxicity [1,2,3,4]. It is often associated with the loss of functional liver cells, activation of hepatic stellate cells (HSC), the senescence of hepatocyte cells and accumulation of extracellular matrix, amongst other detrimental processes [3,4,5,6]. Human amniotic membrane-derived mesenchymal stem cells (hAMCs) have the potential to reduce heart and lung fibrosis, but whether could reduce liver fibrosis remains largely unknown
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