Cell Surface Heparan Sulfate Proteoglycans Mediate the Internalization of PDX-1 Protein
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Although islet transplantation is a promising therapeutic option for the treatment of type 1 diabetes, the shortage of suitable donor tissues remains a major obstacle. Pancreatic stem/progenitor cells residing within the ductal epithelium have been used to generate human islet-like
clusters, but there is no efficient strategy for facilitating differentiation of progenitor cells into insulin-producing cells. A previous study reported that exogenous PDX-1 protein can be transduced into pancreatic stem/progenitor cells and induce differentiation of the cells into insulin-producing
cells without requiring gene transfer technology. This study provides genetic and biochemical evidence that cell membrane heparan sulfate proteoglycans are required for extracellular PDX-1 internalization. Heparin, one of the soluble glycosaminoglycans (GAGs), inhibited PDX-1 internalization,
while chondroitin sulfate A, B, and C caused only very limited inhibition. Cell treatment with heparinase-III demonstrated impaired PDX-1 internalization, while treatment with chondroitinase ABC, or with chondroitinase AC, was completely ineffective in inhibiting PDX-1 internalization. Different
mutant cell lines originating from CHO K1 cells and defective in GAG biosynthesis were also examined. PDX-1 internalization was significantly reduced in both pgs A-745 mutant cells, which are defective in a enzyme that initiates GAG synthesis, and pgs B-618 cells, which produce about 15% of
the amount of GAGs synthesized by wild-type cells. These data indicate that cell-surface heparan sulfate proteoglycans are required for PDX-1 internalization and that PDX-1 protein transduction could be a valuable strategy for inducing insulin expression in pancreatic stem/progenitor cells
without requiring gene transfer technology.
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Keywords:
Heparan sulfate proteoglycan (HSP);
Pancreatic and duodenal homeobox factor-1 (PDX-1);
Protein transduction domain;
Protein transduction technology
Document Type: Research Article
Affiliations:
1:
Fujita Health University, Second Department of Surgery, Aichi 470-1192, Japan, Department of Transplantation and Immunology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
2:
Fujita Health University, Second Department of Surgery, Aichi 470-1192, Japan, Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA
3:
Department of Advanced Medicine in Biotechnology and Robotics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
4:
Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
5:
*Fujita Health University, Second Department of Surgery, Aichi 470-1192, Japan, Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA, Department of Advanced Medicine in Biotechnology and Robotics, Nagoya
University Graduate School of Medicine, Nagoya 466-8550, Japan
Publication date:
01 January 2008