Regional and transient ischemia/reperfusion injury in the liver improves therapeutic efficacy of allogeneic intraportal hepatocyte transplantation in low-density lipoprotein receptor deficient Watanabe rabbits

Abstract

Hepatocyte transplantation has the potential to become an alternative to organ transplantation for the treatment of hereditary liver disease. Currently used hepatocyte transplantation techniques are often not sufficient for phenotypic correction. In a pre-clinical model we investigated the effect of regional transient ischemia reperfusion injury and repeated infusions of allogeneic hepatocytes on LDL cholesterol levels in LDL receptor deficient hyperlipidemic Watanabe rabbits. A catheter was surgically inserted into the inferior mesenteric vein. Blood supply to the right liver lobe was transiently interrupted. Nine infusions of 2.5x10(7) adult allogeneic hepatocytes from white New Zealand rabbits were applied over a period of 2 months. Compared to pretreatment levels LDL cholesterol decreased significantly in Watanabe rabbits with transient ischemia reperfusion injury and repeated hepatocyte transplantation (-42+/-3%). Repeated hepatocyte transplantation without transient ischemia reperfusion injury decreased LDL cholesterol levels only moderately (-11+/-4%). LDL receptor messenger RNA and proteins were detected in hepatocyte transplanted liver but not in the liver of sham treated animals. Our data indicate that transient ischemia reperfusion injury of the recipient liver is safe and significantly improves the therapeutic efficacy of allogeneic hepatocyte transplantation in hyperlipidemic rabbits with congenital LDL receptor deficiency.