Feasibility of hepatocyte transplantation-based therapies for primary hyperoxalurias.
Primary hyperoxalurias (PHs) are diseases caused by overproduction of oxalate by hepatocytes. Most patients with PHs develop nephrocalcinosis and renal failure. Combined liver-kidney transplantation is often used as a definitive treatment of PHs, but because of a large body oxalate load at the time of transplantation, the procedure is not always successful. Because all hepatocytes overproduce oxalate, partial liver replacement procedures, such as auxiliary transplantation of a liver lobe or hepatocyte transplantation are not expected to be useful in this disorder. In this paper we describe novel techniques, based on preparative hepatic irradiation and stimulation of hepatocyte mitosis, through loss of liver mass or administration of hepatic growth factor, which permit transplanted wild-type hepatocytes to massively repopulate the liver, replacing up to 90% of the hepatocytes in recipient mouse livers. Application of this procedure in a recently developed Agxt-gene-deleted mouse model of PH1 resulted in marked amelioration of hyperoxaluria. We propose that further refinement of the different components of this procedure may permit early cell-based therapies of PHs, thereby preventing renal failure and its complications.
Guha
Chandan
C
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, NY, USA.
Yamanouchi
Kosho
K
Jiang
Jinlan
J
Wang
Xia
X
Roy Chowdhury
Namita
N
Santana
Alfredo
A
Shapiro
Lawrence J
LJ
Salido
Eduardo
E
Roy-Chowdhury
Jayanta
J
D000818:Animals; D017690:Cell Transplantation / Q000379:methods*; D005240:Feasibility Studies; D005260:Female; D022781:Hepatocytes / Q000637:transplantation*; D006960:Hyperoxaluria, Primary / Q000628:therapy*; D008115:Liver Regeneration; D008297:Male; D051379:Mice