Transplantation of Human Amnion Epithelial Cells Reduces Hepatic Fibrosis in Immunocompetent CCl₄-Treated Mice

Abstract

Chronic liver injury and inflammation lead to hepatic fibrosis, cirrhosis, and liver failure. Embryonic and mesenchymal stem cells have been shown to reduce experimental liver fibrosis but have potential limitations, including the formation of dysplastic precursors, tumors, and profibrogenic cells. Other stem-like cells may reduce hepatic inflammation and fibrosis without tumor and profibrogenic cell formation. To test this hypothesis we transplanted human amnion epithelial cells (hAEC), isolated from term delivered placenta, into immunocompetent C57/BL6 mice at week 2 of a 4-week regimen of carbon tetrachloride (CCl4) exposure to induce liver fibrosis. Two weeks following hAEC infusion, intact cells expressing the human-specific markers inner mitochondrial membrane protein and human leukocyte antigen-G were found in mouse liver without evidence of host rejection of the transplanted cells. Human albumin, known to be produced by hAEC, was detected in sera of hAEC-treated mice. Human DNA was detected in mouse liver and also spleen, lungs, and heart of some animals. Following hAEC transplantation, CCl4-treated animals showed decreased serum ALT levels and reduced hepatocyte apoptosis, compared to controls. hAEC-treated mouse liver had lower TNF-α and IL-6 protein levels and higher IL-10 compared to animals given CCl4 alone. Compared to CCl4 controls, hAEC-treated mice showed fewer activated collagen-producing hepatic stellate cells and less fibrosis area and collagen content. Reduced hepatic TGF-β levels in conjunction with a twofold increase in the active form of the collagen-degrading enzyme matrix metalloproteinase-2 in hAEC-treated mice compared to CCl4 controls may account for the reduction in fibrosis. hAEC transplantation into immunocompetent mice leads to cell engraftment, reduced hepatocyte apoptosis, and decreased hepatic inflammation and fibrosis.

Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells

“…53 In detail, AM-hMSCs may mediate the tumortargeting effects of immunocytes by regulating the expressions of various cytokines such as tumor necrosis factor-a and ILs. 55 For instance, ILs may help immune systems by activating natural killer cells that can directly target human cancers. The results from these studies demonstrated that hAMS and hAFS have potential antitumor effects.…”

Therapeutic Strategies of Stem Cell Transplantation for Liver Cirrhosis

“…Based on these findings it was postulated that its therapeutic effect might be due to paracrine activation rather than to the hAECs per se. Other workers have shown that hAECs injection improves liver function, reduces hepatocyte apoptosis, and decreases hepatic inflammation and fibrosis in a CCL4-induced liver fibrosis model in wild-type mice [87]. In this study no obvious rejection response was seen 2 weeks after hAECs transplantation.…”

Cell Transplantation: A Possible Alternative to Orthotopic Liver Transplant (OLT)

“…Important for the treatment of liver diseases by CTx, AE cells demonstrate hepatic gene expression and functions at a level of mature hepatocytes following implantation into the livers of SCID mice, which suggest they differentiate into hepatocyte-like cells once engrafted in the liver parenchyma (Miki & Strom, 2006;Marongiu et al, 2011). Undifferentiated AE cells were able to functionally engraft into the livers of immunocompromised mouse models of liver damage resulting in a reduction of hepatic fibrosis, inflammation, and hepatocyte apoptosis (Manuelpillai et al, 2010;Marongiu et al, 2011). In addition, AE cells have also been used in clinics to correct lysosomal storage diseases with no adverse effects (Yeager et al, 1985;Scaggiante et al, 1987;Sakurgawa et al, 1992).…”