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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

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

Inducing autologous liver cells to differentiate into endocrine β 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 × 10e11 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.

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Acknowledgments

The authors are grateful to Drs. I. Rofiq and H. Watada for gifts of pdx-1 construct and Professor Christopher V. E. Wright for gifts of polyclonal anti-rabbit pdx-1 antibody. This study was supported by the RGC Grant HKU 7368/02M to R. Xu and K. S. Lam.

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Authors and Affiliations

  1. Gene Therapy Laboratory, Genome Research Centre, The University of Hong Kong, Hongkong, P.R. China

    Hua Li, Xinyan Li & Ruian Xu

  2. Pharmacology Department, Pharmaceutical College, Dalian Medical University, Dalian, Liaoning, P.R. China

    Hua Li

  3. Pharmaceutical College, Shanghai JiaoTong University, Shanghai, P.R. China

    Xinyan Li

  4. Department of Medicine, The University of Hong Kong, Hongkong, P.R. China

    Karen S. L. Lam

  5. Department of Clinical Biochemistry, The University of Hong Kong, Hongkong, P.R. China

    Sidney Tam

  6. Department of Pediatrics, University of Pennsylvania, Philadelphia, USA

    Weidong Xiao

  7. Molecular Medicine Research Center, Ministry of Education, Quanzhou, Fujian, 362021, P.R. China

    Ruian Xu

  8. Institute of Molecular Medicine, Huaqiao University, Quanzhou, Fujian, 362021, P.R. China

    Ruian Xu

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  1. Hua Li
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  2. Xinyan Li
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  3. Karen S. L. Lam
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  4. Sidney Tam
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Correspondence to Ruian Xu.

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Hua Li and Xinyan Li equally contributed to this work.

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Li, H., Li, X., Lam, K.S.L. et al. 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, 487–497 (2008). https://doi.org/10.1007/s11373-008-9233-3

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  • DOI: https://doi.org/10.1007/s11373-008-9233-3

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