Transplanted Human Amniotic Membrane-Derived Mesenchymal Stem Cells Ameliorate Carbon Tetrachloride-Induced Liver Cirrhosis in Mouse

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.

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

“…Furthermore, more extensive studies documented the various differentiations of hAECs into neuron, astrocytes, pancreatic cells, cardiomyocytes, myocytes, osteocytes and adipocytes. 30 Human amniotic membrane-derived MSCs (AM-hMSCs) Amniotic membrane-human MSCs are isolated from amniotic membrane 8,16,24,26 and named AM-hMSCs. AM-hMSCs can be obtained after in vitro culture of term amnion.…”

“…21,32 In terms of differentiation potential, AMhMSCs were shown to differentiate in culture toward different cell types such as adipogenic, chondrogenic, osteogenic, skeletal-and cardio-myogenic, endothelial cells, hepatocyte-like cells and neuroglial cells. 33 Zhang et al 26 have reported that the transplantation of AM-hMSCs significantly decreased hepatic fibrosis and progression of CCl 4 -induced cirrhosis, thereby providing a new approach for the treatment of fibrotic liver disease. In addition, when transplanted in rat heart, they were also shown to survive and to achieve cardiac differentiation without immunological rejection.…”

How do Mesenchymal Stem Cells Repair?

“…Studies show that MSC are capable of inhibiting apoptosis in kidney, liver and brain injuries (30,(131)(132)(133). Recent evidence shows that this is done through increasing prosurvival factors as Akt expression in injured cells (55), BDNF and growth factors as IGF, VEGF and HGF expression which inhibit apoptosis and stimulate cell proliferation (134,135).…”

Antifibrotic Activity of Human Placental Amnion Membrane-Derived CD34+ Mesenchymal Stem/Progenitor Cell Transplantation in Mice With Thioacetamide-Induced Liver Injury

“…The multipotent differentiation capacity of human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) has been reported recently, and studies support their candidacy as a suitable source for cell-based therapy [14][15][16][17][18]. Analogous to bone marrow-derived cells, hAM-MSCs exhibit self-renewal ability, strong immunosuppressive function, freedom from ethical concerns, and easy accessibility and can be induced to various cell types, including the hepatic lineage [19].…”