Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium

To establish the process by which transplanted cells integrate into the liv er parenchyma, we used dipeptidyl peptidase IV-deficient F344 rats as hosts . On intrasplenic injection, transplanted hepatocytes immediately entered l iver sinusoids, along with attenuation of portal vein radicles on angiograp hy. However, a large fraction of transplanted cells (>70%) was rapidly clea red from portal spaces by phagocyte/macrophage responses. On the other hand , transplanted hepatocytes entering the hepatic sinusoids showed superior s urvival. These cells translocated from sinusoids into liver plates between 16 and 20 hours after transplantation, during which electron microscopy sho wed disruption of the sinusoidal endothelium. Interestingly, production of vascular endothelial growth factor was observed in hepatocytes before endot helial disruptions. Portal hypertension and angiographic changes resulting from cell transplantation resolved promptly. Integration of transplanted he patocytes in the liver parenchyma required cell membrane regenesis, with hy brid gap junctions and bile canaliculi forming over 3 to 7 days after cell transplantation. We propose that strategies to deposit cells into distal he patic sinusoids, to disrupt sinusoidal endothelium for facilitating cell en try into liver plates, and to accelerate cell integrations into liver paren chyma will advance applications of hepatocyte transplantation.