Hepatocyte transplantation improves survival in mice with liver toxicity induced by hepatic overexpression of Mad1 transcription factor.
Hepatic overexpression of Mad1 with an adenoviral vector, AdMad, induced liver toxicity in immunodeficient mice. Transduction of cultured hepatocytes with AdMad inhibited cellular DNA synthesis and cell cycling, along with increased lactate dehydrogenase release, indicating cytotoxicity. When dipeptidyl peptidase IV-deficient F344 rat hepatocytes were transplanted into the liver of immunodeficient mice after treatment with AdMad, significant portions of the liver were repopulated. This was in agreement with corresponding losses of host hepatocytes, which showed increased apoptosis rates. Mortality in mice following AdMad treatment decreased significantly when animals were subjected to hepatocyte transplantation. The findings indicated that Mad1 overexpression perturbed hepatocyte survival. Investigation of pathophysiological mechanisms concerning specific cell cycle regulators in acute liver toxicity will thus be appropriate. Cell therapy has potential for treating acute liver injury under suitable circumstances.
Gagandeep
S
S
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Sokhi
R
R
Slehria
S
S
Gorla
G R
GR
Furgiuele
J
J
DePinho
R A
RA
Gupta
S
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017690:Cell Transplantation; D015870:Gene Expression; D006801:Humans; D007763:Lac Operon; D008099:Liver / Q000378:metabolism; D017114:Liver Failure, Acute / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D016031:Liver Transplantation; D051379:Mice; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C501385:Mad1l1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins