Amplification of engrafted hepatocytes by preparative manipulation of the host liver

Scarcity of donor livers is a major obstacle to the general application of hepatocytes for the development of bioartificial liver assist devices as we ll as intracorporeal engraftment of hepatocytes for the treatment of inheri ted metabolic diseases. The number of hepatocytes that can be transplanted into the liver safely in a single sitting also limits the utility of this p rocedure. These limitations could be addressed by providing preferential pr oliferative advantage to the transplanted cells. Studies using transgenic m ouse recipients or donors have indicated that massive repopulation of the h ost liver by engrafted hepatocytes requires that the transplanted cells are subjected to a proliferative stimulus to which the host hepatocytes cannot respond. Prevention of host hepatocyte proliferation has been achieved by treatment with a plant alkaloid, retrorsine. Because retrorsine is carcinog enic, we have evaluated preparative irradiation for this purpose. The proli ferative stimulus may consist of the loss of hepatic mass (e.g., partial he patectomy, reperfusion injury or induction of Fas-mediated apoptosis by gen e transfer) or administration of stimulants of hepatocellular mitosis (e.g. , growth factors or thyroid hormone). Potential applications of these prepa rative manipulations of the host liver include the treatment of inherited m etabolic disorders by transplantation of allogeneic hepatocytes, hepatocyte -mediated ex vivo gene therapy, rescuing liver cancer patients from radiati on-induced liver damage, and expansion of human hepatocytes in animal liver s.