Long-term correction of albumin levels in the Nagase analbuminemic rat: repopulation of the liver by transplanted normal hepatocytes under a regeneration response.

Abstract

Numerous studies have reported successful transplantation of hepatocytes with demonstration of function. However, none have shown long-term correction of a liver-related metabolic defect. Male Nagase analbuminemic rats, immunosuppressed with cyclosporin-A, were transplanted with normal hepatocytes (2 x 10(7) cells/rat) isolated from allogeneic male Sprague-Dawley rat donors. Hepatocytes were selectively transplanted via the portal vein tributary into the posterior liver lobes of Nagase analbuminemic rats. Following 2 wk, to allow engraftment, selected transplanted rats (Group I) were reoperated and the portal venous branch supplying the anterior liver lobes was permanently ligated, resulting in their atrophy and induction of regeneration in the residual transplant-bearing lobes. Control rats consisted of: Group II-transplanted with normal hepatocytes without portal branch ligation; Group III-transplanted with analbuminemic hepatocytes with portal branch ligation; and Group IV-nontransplanted analbuminemic rats with portal branch ligation. The experimental period extended to 3 mo posttransplantation. All rats transplanted with normal hepatocytes demonstrated a significant elevation in serum albumin levels (ELISA). Group I rats had dramatic elevations in serum albumin to near normal levels (1.78 +/- 0.20 g/dl), and maintained these levels until the end of the experiment. Albumin levels in Group II rats reached 0.26 +/- 0.07 g/dl (p < 0.001), whereas Group III and IV rats showed no changes in serum albumin levels throughout the experiment. Immunohistology of liver tissue obtained from Group I rats, demonstrated large numbers (22.6 +/- 7.5%) of albumin-positive hepatocytes populating the recipient liver. This is the first report of near-total and sustained correction of a genetic defect in liver function in an experimental animal model following allogeneic hepatocyte transplantation.