Abstract
To improve the therapeutic potential of hepatocyte transplantation, the effects of the mitogen-activated protein kinase kinase 4 (MKK4) inhibitor, myricetin (3,3′,4′,5,5′,7-hexahydroxylflavone) were examined using porcine and human hepatocytes in vitro and in vivo. Hepatocytes were cultured, showing the typical morphology of hepatic parenchymal cell under 1–10 µmol/L of myricetin, keeping hepatocyte specific gene expression, and ammonia removal activity. After injecting the hepatocytes into neonatal Severe combined immunodeficiency (SCID) mouse livers, cell colony formation was found at 10–15 weeks after transplantation. The human albumin levels in the sera of engrafted mice were significantly higher in the recipients of myricetin-treated cells than non-treated cells, corresponding to the size of the colonies. In terms of therapeutic efficacy, the injection of myricetin-treated hepatocytes significantly prolonged the survival of ornithine transcarbamylase-deficient SCID mice from 32 days (non-transplant control) to 54 days. Biochemically, the phosphorylation of MKK4 was inhibited in the myricetin-treated hepatocytes. These findings suggest that myricetin has a potentially therapeutic benefit that regulates hepatocyte function and survival, thereby treating liver failure.
Highlights
Orthotopic liver transplantation has been successful in the treatment of a variety of end-stage liver diseases [1,2]
Our findings demonstrate that myricetin could be used as a preconditioning treatment in order to improve the success rate of cell transplantation therapies
Cryopreserved hepatocytes of a neonatal kusabira orange transgenic pig were cultured and showed the typical morphology of hepatic parenchymal cell with myricetin (Figure 1)
Summary
Orthotopic liver transplantation has been successful in the treatment of a variety of end-stage liver diseases [1,2]. The conditions under which patients require liver transplantation involve diseases that range from acute to chronic liver failure. The former is generally characterized by a rapid deterioration in total liver function, resulting in coagulopathy and encephalopathy; the latter develops slowly but irreversibly as seen with cholestatic liver disease, cirrhosis, and congenital metabolic disorders. Pediatricians are tasked with preventing the affected babies from hyperammonemia until they are old enough to undergo transplantation surgery. In these cases, hepatocyte transplantation offers a novel treatment to maintain low blood ammonia levels in patients not suitable for liver transplantation
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