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PMID:18253862

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Citation

Li, H, Li, X, Lam, KS, Tam, S, Xiao, W and Xu, R (2008) Adeno-associated virus-mediated pancreatic and duodenal homeobox gene-1 expression enhanced differentiation of hepatic oval stem cells to insulin-producing cells in diabetic rats. J. Biomed. Sci. 15:487-97

Abstract

Inducing autologous liver cells to differentiate into endocrine beta cell has been a potential strategy for the treatment of type 1diabetes. However it is still not known which sub-population cells in the liver was responsible for this developmental shift. Pancreatic and duodenal homeobox gene 1 (pdx-1), a crucial transcription factor in pancreatic islet development and differentiation, has attracted much interests in beta cell differentiation experiments. This study was conducted to evaluate whether pdx-1 gene delivered by adeno-associated virus (AAV) could induce autologous liver cells to differentiate into insulin-producing cells and to explore the origin of these cells. Here we used 4 x 10e(11) AAV to deliver pdx-1 to STZ-induced diabetic rats via the portal vein. Immunofluorescent staining showed more insulin-positive cells, which had similar morphology with hepatic oval stem cells and were positive for hepatic oval stem cell markers, Thy-1 and cytokeratin 19 (ck19). In addition to the expression of pdx-1, insulin1 and insulin2, RT-PCR and quantitative real-time PCR also detected significantly higher levels of other important transcription factors in AAV-pdx-1 treated diabetic rat livers. AAV-pdx-1 treated diabetic rats showed partially ameliorated hyperglycemia, better gain of body weight and improved lipid levels. Our data indicated that rat hepatic oval stem cells were differentiated into bioactive insulin-producing cells by AAV-pdx-1 delivery in diabetic rats, with promoted expression of some transcription factors necessary for beta cell development and function.

Links

PubMed Online version:10.1007/s11373-008-9233-3

Keywords

Animals; Biological Markers/analysis; Body Weight; Cell Differentiation; Dependovirus/genetics; Diabetes Mellitus, Experimental/therapy; Duodenum/metabolism; Gene Therapy; Genes, Homeobox/genetics; Genetic Vectors; Hepatocytes/cytology; Hyperglycemia; Insulin-Secreting Cells/cytology; Lipid Metabolism; Male; Pancreas/metabolism; Rats; Rats, Sprague-Dawley; Stem Cells/cytology; Transcription Factors/genetics; Treatment Outcome

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:PDX1

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:PDX1

involved_in

GO:0048863: stem cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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