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.
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.
Li
Hua
H
Gene Therapy Laboratory, Genome Research Centre, The University of Hong Kong, Hongkong, PR China.
Li
Xinyan
X
Lam
Karen S L
KS
Tam
Sidney
S
Xiao
Weidong
W
Xu
Ruian
R
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001835:Body Weight; D002454:Cell Differentiation; D000229:Dependovirus / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D004386:Duodenum / Q000378:metabolism*; D005801:Genes, Homeobox / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D022781:Hepatocytes / Q000166:cytology; D006943:Hyperglycemia; D050417:Insulin-Secreting Cells / Q000166:cytology*; D050356:Lipid Metabolism; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome
D015415:Biomarkers; D014157:Transcription Factors