Animals comprising human hepatocellular tissue

Abstract

Non-human mammalian hosts are provided, comprising functional human hepatocytes. Isolated human hepatocytes or fragments of human hepatic tissue are introduced into the xenogeneic host in conjunction with one or more agent that stimulates human hepatocyte growth factor receptor. The human hepatocytes are maintained in the host by administration of one or more agent that stimulates human hepatocyte growth factor receptor, either continuously (e.g., via an implanted catheter or intravenous apparatus) or in discrete, regular dosages of the agent (e.g., via intravenous injections or oral dosages). The human hepatocytes are able to survive and function in the host animal for a period of at least 5 months.

That which is claimed is:  
     
         1 . A non-human mammalian host comprising: 
 engrafted functional human hepatocytes; and    introduced human hepatocyte growth factor receptor activator.    
     
     
         2 . The host of  claim 1 , wherein the human hepatocytes are maintained in the host for a period of at least five months.  
     
     
         3 . The host of  claim 1 , wherein the human hepatocytes are maintained in said host by administration of said human hepatocyte growth factor receptor activator.  
     
     
         4 . The host of  claim 3 , wherein said human hepatocyte growth factor receptor activator is administered by dosage at regular intervals following transplantation.  
     
     
         5 . The host of  claim 3 , wherein said human hepatocyte growth factor receptor activator is administered continuously following transplantation.  
     
     
         6 . The host of  claim 1 , wherein the agent is an antibody that specifically binds human c-Met.  
     
     
         7 . The host of  claim 6 , wherein the antibody specifically binds to an epitope on the extracellular domain of human hepatocyte growth factor receptor.  
     
     
         8 . The host of  claim 1 , wherein said human hepatocyte growth factor receptor activator is selected from the group consisting of: human hepatocyte growth factor, human hepatocyte growth factor receptor, a constitutively activated human hepatocyte growth factor receptor, and a small molecule that activates human hepatocyte growth factor receptor.  
     
     
         9 . The host of  claim 1 , wherein factors other than the human hepatocyte growth factor receptor are administered to said host.  
     
     
         10 . The host of  claim 9 , wherein an angiogenic factor is administered to said host prior to transplantation.  
     
     
         11 . The host of  claim 1 , wherein the host liver is partially removed prior to transplantation.  
     
     
         12 . The host of  claim 1 , wherein the host is a mammal from the genus Rodentia.  
     
     
         13 . The host of  claim 12 , wherein the host is a mouse.  
     
     
         14 . The host of  claim 13 , wherein the mouse is immunocompromised.  
     
     
         15 . The host of  claim 14 , wherein the mouse is homozygous for a mutation at the scid locus.  
     
     
         16 . A method for producing a chimeric non-human mammalian host comprising functional human hepatocytes, said method comprising: 
 introducing human hepatocytes into the host; and    introducing a human hepatocyte growth factor receptor activator to said host in an amount sufficient to allow engraftment of said human hepatocytes    maintaining said host for a period allowing for engraftment of human hepatocytes.    
     
     
         17 . The method of  claim 16 , wherein said period allowing for engraftment is between about 2 and about 4 weeks.  
     
     
         18 . The method of  claim 16 , wherein the human hepatocytes are introduced under the kidney capsule.  
     
     
         19 . The method of  claim 16 , wherein the human hepatocytes are introduced at a subcutaneous site.  
     
     
         20 . The method of  claim 16 , the method further comprising: 
 treating a transplantation site with an angiogenic factor; wherein said human hepatocytes are introduced to the treated transplantation site.    
     
     
         21 . The method of  claim 16 , further comprising performing a partial hepatectomy to the host prior to the introduction of human hepatocytes.  
     
     
         22 . The method of  claim 16 , wherein the host is from the genus Rodentia.  
     
     
         23 . The method of  claim 16 , wherein the host is a mouse.  
     
     
         24 . The method of  claim 23 , wherein the agent is an antibody directed against the extracellular domain of c-Met.  
     
     
         25 . A method for screening agents, said method comprising: 
 administering said agent to a non-human mammalian host comprising engrafted functional human hepatocytes and an activator of human hepatocyte growth factor receptor; and    determining the effect of said agent on said human hepatocytes.    
     
     
         26 . The method of  claim 25 , wherein the host is infected with a pathogen.  
     
     
         27 . The method of  claim 26 , wherein the pathogen is a viral pathogen selected from the group consisting of Hepatitis B, Hepatitis C and Hepatitis D.  
     
     
         28 . The method of  claim 26 , wherein the pathogen is a parasitic pathogen having a developmental stage in the human liver.  
     
     
         29 . The method of  claim 25 , wherein the agent is a chemical toxin.  
     
     
         30 . The method of  claim 25 , wherein the agent is a candidate therapeutic agent.  
     
     
         31 . The method of  claim 30 , wherein the hepatocytes are infected with one or more pathogen.