Transplantation of hepatocytes in nonhuman primates: A preclinical model for the treatment of hepatic metabolic diseases.

Background. The transplantation of isolated hepatocytes in large animals, i ncluding nonhuman primates, must be evaluated before clinical trials are pe rformed. However, in the absence of large transgenic animals and large-anim al (as opposed to small-animal) models of genetic deficiencies, it is diffi cult to evaluate the fate of transplanted hepatocytes, their localization, survival, and function within the parenchyma of the host liver. In this wor k, we aimed to develop a technique for delivering hepatocytes to the liver of a nonhuman primate and to evaluate their localization and functionality in the short term. Methods. A 20% hepatectomy was performed in 34 cynomolgus monkeys (Macaca f ascicularis) and hepatocytes were isolated. Hepatocytes were labeled in vit ro with a recombinant retrovirus expressing the beta -galactosidase gene an d returned to the liver by infusion through a portal catheter left in place . Liver biopsies were performed 4 and 7 d after transplantation. Results. Twenty-four monkeys underwent surgery to define the necessary tech nical adjustments and to optimize conditions. Six monkeys died. The whole p rotocol, including the transplantation of genetically marked hepatocytes an d procurement of liver biopsies, was performed in the remaining 10 monkeys. In eight monkeys, transplanted hepatocytes expressing the beta -galactosid ase gene were widely distributed in the portal tracts, sinusoids, and hepat ocyte plates of the host liver 4 and 7 d after transplantation. Conclusions. We have developed an experimental nonhuman primate model for t he evaluation of hepatocyte transplantation. We demonstrated the engraftmen t and functioning of transplanted hepatocytes in the host liver 4 and 7 d a fter transplantation.