Rapid clearance of transplanted hepatocytes from pulmonary capillaries in rats indicates a wide safety margin of liver repopulation and the potential of using surrogate albumin particles for safety analysis

Abstract

Background/Aims: Applications of liver repopulation by hepatocyte transplantation require analysis of cell biodistributions, particularly when portasystemic shunting coexists. The aims of this study were to determine the fate of hepatocytes transplanted into the pulmonary vascular bed and to examine whether cell biodistributions could be approximated by convenient surrogates.Methods: Rat hepatocytes and macroaggregated serum albumin particles of similar sizes were injected into the portal and pulmonary vascular beds of rats, followed by biodistribution, survival and function analyses.Results: Although functionally intact, virtually all hepatocyteswere cleared from the pulmonary capillaries within 24 h. Serum albumin levels increased minimally in Nagase analbuminemic rats with or without portacaval shunting to enhance delivery of portal factors to transplanted cells in lungs. Despite intravenous injection of hepatocytes approaching >1×109 cells in humans, the hemodynamic changes were limited to transient increases in right atrial pressures. The hepatocyte distributions in specific vascular beds were largely reproduced by macroaggregated human serum albumin particles.Conclusions: Incidental intrapulmonary cell translocations during liver repopulation will have a wide safety margin. Use of macroaggregated serum albumin particles as surrogates for initial short-term biodistribution and safety analysis will advance hepatocyte transplantation, as the cost of GLP-certified laboratories and consumption of scarce donor livers will be avoided.