Propagation of human hepatocytes in non-human animals
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Abstract
The present invention relates to the preparation of non-human animals having chimeric livers, whereby some or substantially all of the hepatocytes present are human hepatocytes. It is based, at least in part, on the discovery that rats, tolerized in utero against human hepatocytes, were found to serve as long-term hosts for human hepatocytes introduced post-natally, and the introduced hepatocytes maintained their differentiated phenotype, as evidenced by continued production of human albumin. The present invention further relates to the use of such animals as models of various liver diseases, including viral invention. Such embodiments are based on the discovery that transplanted human hepatocytes in chimeric livers were found to be susceptible to Hepatitis B virus and Hepatitis C virus infection.
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Citations
33 Claims
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1-5. -5. (Canceled)
- 6. A non-human mammal having a chimeric liver comprising human hepatoblastoma cells.
- 14. A method of preparing a non-human mammal having a chimeric liver comprising human hepatoblastoma cells, the method comprising introducing human hepatoblastoma cells into the mammal, wherein the number of introduced cells is effective in colonizing the liver of the mammal.
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25. A method for identifying a toxic effect of a test agent, the method comprising administering the test agent to a non-human mammal having a chimeric liver comprising human hepatoblastoma cells, and subsequently evaluating whether changes have occurred in the viability of the human hepatoblastoma cells.
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26. A method for determining a toxic effect of a test agent on a non-human mammal, the method comprising administering the test agent on the mammal, performing a toxicology test on the mammal, and determining whether the test agent has a toxic effect on the mammal, wherein a positive score on the test indicates a toxic effect of the test agent on the mammal, and wherein the mammal has a chimeric liver comprising human hepatoblastoma cells.
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27. A method for determining the metabolic fate of a test agent on a non-human mammal of one species, the method comprising administering the test agent on the mammal and performing an assay that determines a metabolite of the test agent, wherein the mammal has a chimeric liver comprising human hepatoblastoma cells, wherein the mammal has received a test agent, wherein the test agent passes through the liver, and wherein the metabolic fate of the test agent in the mammal substantially recapitulates the metabolic fate of the test agent in a normal mammal of the respective species.
- 29. A model system for a human liver disease comprising a non-human mammal having a chimeric liver comprising human hepatoblastoma cells, wherein a toxin or pathogen is introduced.
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30. A model system for alcohol-associated liver disease comprising a non-human mammal having a chimeric liver comprising human hepatoblastoma cells, wherein the mammal has been administered an amount of alcohol effective in producing hepatocellular degenerative changes.
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31. A toxicology model system comprising a non-human mammal having a chimeric liver comprising human hepatoblastoma cells, wherein the mammal has received a test agent.
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32. A model system comprising a non-human mammal of one species, wherein the mammal has a chimeric liver comprising human hepatoblastoma cells, wherein the mammal has received a test agent, wherein the test agent passes through the liver, and wherein the model system substantially recapitulates the metabolic fate of the test agent in a normal mammal of the respective species.
Specification