A novel strategy for in vivo expansion of transplanted hepatocytes using preparative hepatic irradiation and FasL-induced hepatocellular apoptosis.
A strategy for inducing preferential proliferation of the engrafted hepatocytes over host liver cells should markedly increase the benefit of hepatocyte transplantation for the treatment of liver diseases and ex vivo gene therapy. We hypothesized that preparative hepatic irradiation (HIR) to inhibit host hepatocellular regeneration in combination with the mitotic stimulus of host hepatocellular apoptosis should permit repopulation of the liver by transplanted cells. To test this hypothesis, congeneic normal rat hepatocytes were transplanted into UDP-glucuronosyltransferase (UGT1A1)-deficient jaundiced Gunn rats (a model of Crigler-Najjar syndrome type I), following HIR and adenovirus-mediated FasL gene transfer. Progressive repopulation of the liver by engrafted UGT1A1-proficient hepatocytes over 5 months was demonstrated by the appearance of UGT1A1 protein and enzyme activity in the liver, biliary bilirubin glucuronides secretion, and long-term normalization of serum bilirubin levels. This is the first demonstration of massive hepatic repopulation by transplanted cells by HIR and FasL-induced controlled apoptosis of host liver cells.
Takahashi
M
M
Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Deb
N J
NJ
Kawashita
Y
Y
Lee
S W
SW
Furgueil
J
J
Okuyama
T
T
Roy-Chowdhury
N
N
Vikram
B
B
Roy-Chowdhury
J
J
Guha
C
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001663:Bilirubin / Q000378:metabolism; D003414:Crigler-Najjar Syndrome / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053222:Fas Ligand Protein; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D014453:Glucuronosyltransferase / Q000172:deficiency; D022781:Hepatocytes / Q000637:transplantation*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D014161:Transduction, Genetic / Q000379:methods
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D014453:Glucuronosyltransferase; D001663:Bilirubin