Normal hepatocytes correct serum bilirubin after repopulation of Gunn rat liver subjected to irradiation/partial resection

Abstract

The treatment of inherited metabolic liver diseases by hepatocyte transplantation (HT) would be greatly facilitated if the transplanted normal hepatocytes could be induced to proliferate preferentially over the host liver cells. We hypothesized that preparative hepatic irradiation ( H epatocyte transplantation (HT) is currently being evaluated as a treatment strategy for patients with acute and chronic liver failure and to replace metabolic liver functions in inherited liver diseases. 1 HT has been used in the treatment of inherited metabolic diseases, such as Crigler-Najjar syndrome type I, 2 and for hepatocyte-based ex vivo gene therapy in experimental animals 3-5 as well as in patients with low-density lipoprotein receptor deficiency. 6 However, the clinical application of HT is limited by the availability of human hepatocytes and the number of liver cells that can be transplanted safely at one time. An important consideration is whether a sufficient number of hepatocytes can be engrafted to achieve the desired metabolic correction without causing portal hypertension or other adverse effects. Therefore, a method to induce preferential proliferation of a relatively small number of engrafted hepatocytes in vivo could markedly enhance the applicability of HT.We hypothesized that preparative irradiation of the liver along with a strong mitotic stimulus provided by a maneuver such as partial hepatectomy (PH) should damage the host hepatocyte DNA, causing cell cycle arrest. Subsequently transplanted normal, nonirradiated hepatocytes should proliferate preferentially in response to the

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…These include genetic diseases that produce liver disease, such as Wilson's disease (copper accumulation), Crigler-Najjar syndrome (lack of bilirubin conjugation activity) and tyrosinaemia, and cases where there is extrahepatic expression of the disease, eg Factor IX deficiency. Transplantation of adult rat hepatocytes has been effective in normalizing bilirubin levels and improving bilirubin conjugation activity in Gunn rats (a model of Crigler-Najjar syndrome) [32,33]. These cells were reversibly immortalized and transduced with the bilirubin-uridine 5 -diphosphoglucuronate glucuronsyltransferase gene (ugt1a1 ) and engraftment was improved by prior irradiation and partial hepatectomy of the recipient rats.…”

Construction of liver tissue in vivo with preparative partial hepatic irradiation and growth stimulus: investigations of less invasive techniques and progenitor cells

“…Selective proliferation of transplanted hepatocytes by providing a growth stimulus by partial hepatectomy of the host liver, combined with hepatic irradiation (HIR) of the whole liver that can suppress proliferation of host hepatocytes, and consequently, almost the whole liver would be constructed with donor hepatocytes (7). Moreover, jaundiced Gunn rats of Crigler-Najjar syndrome type I model, which lack hepatic uridinediphosphoglucuronate glucuronosyltransferase (UGT1A1) activity, had UGT1A1 protein and enzymatic activity in the liver, and normalization of serum bilirubin levels (8). Although these results are very attractive, hepatectomy is too invasive to be carried out in patients.…”

A novel strategy for in vivo expansion of transplanted hepatocytes using preparative hepatic irradiation and FasL-induced hepatocellular apoptosis

“…Our study provides a proof of the principle that Fasmediated hepatocellular apoptosis can be used as a noninvasive alternative to PH, 11 which, in combination with HIR, permits massive hepatic repopulation by engrafted hepatocytes. The FasL-expressing adenoviral vector system was used as a convenient experimental tool to induce Fas-activated hepatocellular apoptosis.…”

“…10 We demonstrated that a regimen of whole liver irradiation and 68% PH, followed by transplantation of normal unirradiated cells, resulted in massive repopulation by the transplanted hepatocytes in the host liver. 11 To extend our observations into potential clinical application of HIR as a preparative regimen for HT, we are seeking an alternative to PH.…”