Animal model for identifying a common stem/progenitor to liver cells and pancreatic cells

Abstract

The invention provides animal models, where the ectopic expression of KGF, EGF, or both is under the control of a pancreas-specific promoter, e.g., the insulin promoter. The expression of KGF in the ins-KGF pancreatic islets of Langerhans results in enlarged islets, with substantial proliferation of duct cells within the islet mass, and the presence of albumin and alpha-fetoprotein-producing hepatocytes in the islets of the ins-KGF pancreata. The compositions and methods disclosed are useful for identifying and isolating pancreatic stem/progenitor cells, including a common stem/progenitor to liver cells and pancreatic cells.

We claim:  
     
         1 . A transgenic non-human mammal, whose cells contain a polynucleotide, comprising: 
 a pancreas-specific promoter operably linked to a KGF-coding polynucleotide.    
     
     
         2 . The transgenic mammal of    claim 1    wherein the pancreas-specific promoter is an insulin promoter.  
     
     
         3 . The mammal of    claim 1    or    2   , whose cells further contain a polynucleotide, comprising: 
 a second pancreas-specific promoter operably linked to an EGF-coding polynucleotide.  
 
     
     
         4 . The mammal of    claim 1    or    2   , whose cells further contain a polynucleotide, comprising: 
 an insulin promoter operably linked to an EGF-coding polynucleotide promoter.  
 
     
     
         5 . A method for the in vivo proliferation of pancreatic duct cells in a mammal, comprising: 
 providing a pancreatic source of KGF to the mammal.    
     
     
         6 . A method for in vivo production of pancreatic hepatocytes in a mammal, comprising: 
 providing a pancreatic source of KGF to the mammal.    
     
     
         7 . The methods of    claim 5    or    6   , wherein the pancreatic source of KGF is provided by expression of a recombinant DNA molecule comprising a pancreatic specific promoter operably linked to a KGF-coding polynucleotide.  
     
     
         8 . A method for producing pancreatic duct cells, comprising 
 contacting a common stem/progenitor cell to liver cells and pancreatic cells with a developmentally effective amount of KGF, wherein KGF induces common stem/progenitor cells to develop to duct cells.    
     
     
         9 . A method for producing amylase-positive exocrine cells, comprising 
 contacting a common stem/progenitor to liver cells and pancreatic cells with a developmentally effective amount of KGF, wherein KGF induces common stem/progenitor cells to develop to exocrine cells.    
     
     
         10 . A method for the in vivo proliferation of a common stem/progenitor to liver cells and pancreatic cells, comprising 
 providing a pancreatic source of KGF a proliferation-inducing growth factor to a mammal, wherein the growth factor is the expression product of a polynucleotide having a pancreatic-specific promoter operably linked with a coding polynucleotide for the growth factor.    
     
     
         11 . The method of    claim 10   , wherein the pancreatic-specific promoter is an insulin promoter.  
     
     
         12 . A method for inhibiting beta cell development in the pancreas of a mammal, comprising: 
 injecting the subject with an inhibition-effective amount of a neutralizing α-KGF antibody.    
     
     
         13 . A method for identifying proliferating pancreatic duct cells using PDX-1 as a marker, comprising: 
 (a) contacting a pancreatic duct containing proliferating pancreatic duct cells with a reagent that binds to PDX-1 and    (b) detecting the contact, wherein the detection identifies the duct as containing proliferating pancreatic duct cells.    
     
     
         14 . The method of    claim 13   , wherein the reagent is an anti-PDX-1 antibody.  
     
     
         15 . The method of    claim 13   , wherein the detection is of contact between the reagent and PDX-1 in a proliferating pancreatic duct cell.  
     
     
         16 . The method of    claim 13   , wherein the proliferating pancreatic duct cell is a pancreatic stem/progenitor cell.  
     
     
         17 . The method of    claim 16   , wherein the detection is of contact between the reagent and PDX-1 in a pancreatic stem/progenitor cell.