Correction of hyperoxaluria by liver repopulation with hepatocytes in a mouse model of primary hyperoxaluria type-1.
BACKGROUND
Primary hyperoxaluria type-1 (PH1) is an autosomal recessive disease characterized by excessive oxalate production by hepatocytes caused by the deficiency of peroxisomal alanine-glyoxylate aminotransferase (AGT) activity. Persistent hyperoxaluria causes nephrocalcinosis and urolithiasis, leading to renal failure, followed by tissue oxalosis with life-threatening complications. Combined liver-kidney transplantation is the only definitive treatment of PH1. Hepatocyte transplantation, which is much less invasive, could have offered an attractive alternative. However, because the AGT-deficient hepatocytes overproduce oxalate, a large fraction of the mutant host hepatocytes must be replaced by AGT-competent cells, which is beyond the capacity of current hepatocyte transplantation procedures. Here, we have evaluated a preparative irradiation-based method of liver repopulation in an Agxt-deleted mouse model of PH1 (Agxt-/-).


METHODS
Hepatocytes (10(6) viable cells) isolated from congeneic mice ([ROSA]26 C57BL/6J) expressing Escherichia coli beta-galactosidase were transplanted into Agxt-/- mice by intrasplenic injection. The preparative regimen consisted of X-irradiation of the host liver and mitotic stimulation of the hepatocytes by adenovector-based expression of hepatocyte growth factor.


RESULTS
The procedure resulted in progressive replacement of the mutant host hepatocytes with the AGT-competent hepatocytes, leading to correction of urinary oxalate excretion. Oral ethylene glycol challenge (0.7% for 1 week) resulted in nephrocalcinosis and microlithiasis in untreated Agxt-/- mice, but not in the mice after hepatic repopulation.


CONCLUSIONS
The results indicate that hepatocyte transplantation after appropriate preparative regimens may permit sufficient repopulation of the liver to ameliorate hyperoxaluria, and therefore should be evaluated further as a potential treatment of PH1.
Jiang
Jinlan
J
Department of Medicine, and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Salido
Eduardo C
EC
Guha
Chandan
C
Wang
Xia
X
Moitra
Rituparna
R
Liu
Laibin
L
Roy-Chowdhury
Jayanta
J
Roy-Chowdhury
Namita
N
D000818:Animals; D004195:Disease Models, Animal; D019855:Ethylene Glycol / Q000008:administration & dosage; D022781:Hepatocytes / Q000201:enzymology / Q000637:transplantation*; D006960:Hyperoxaluria, Primary / Q000601:surgery*; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009397:Nephrocalcinosis / Q000209:etiology; D000637:Transaminases / Q000172:deficiency; D014184:Transplantation, Homologous; D001616:beta-Galactosidase / Q000378:metabolism
D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; D001616:beta-Galactosidase; D019855:Ethylene Glycol