Background
Cell therapy is considered a potential alternative to liver transplantation in acute liver failure (ALF). We aimed to evaluate the add-on therapeutic benefit of hepatocyte and mesenchymal stem cell (MSC) cotransplantation over hepatocyte-only transplantations in a rat model of ALF.
Conclusions
Hepatocyte and MSC cotransplantation is feasible and safe in rat models of ALF. MSCs were found to survive the process and could be located within the periportal niches 2 weeks after treatment, without enhancing transplanted hepatocyte proliferation or differentiating into hepatocytes, while ameliorating the inflammatory response.
Methods
ALF was induced by D-galactosamine in Sprague-Dawley rats. Freshly isolated donor hepatocytes were derived from Tg (UBC-emGFP) rats and MSCs were collected from the bone marrow cells of DsRed rats. Donor hepatocytes (1×107/mL) were intraportally transplanted 24 hours after treatment with D-galactosamine over a 70-second interval, and donor MSCs (0.5, 1, or 2×106/0.5 mL) were intraportally transplanted 1 hour after the hepatocyte transplantation was complete. Animals were sacrificed after 7 and 14 days and subjected to donor cell identification, liver histology, serologic testing, and immunohistopathological examination.
Results
MSCs were observed in the periportal area, 1 and 2 weeks after transplantation. Transplanted hepatocytes did not actively proliferate when compared to hepatocyte-only transplantation. Morphologically, transplanted MSCs did not appear to differentiate into hepatocytes even 2 weeks after transplantation. Cotransplantation of MSCs was associated with lower macrophage infiltration, and reduced type I collagen, hepatocyte growth factor, tumor necrosis factor-α, and interleukin 10 expression, with similar gene expression profiles for epidermal growth factor and interleukin 6, when compared to hepatocyte-only transplantation. Conclusions: Hepatocyte and MSC cotransplantation is feasible and safe in rat models of ALF. MSCs were found to survive the process and could be located within the periportal niches 2 weeks after treatment, without enhancing transplanted hepatocyte proliferation or differentiating into hepatocytes, while ameliorating the inflammatory response.