Diabetes mellitus is manifested as a reduction in insulin delivery required to maintain glucose homeostasis. A major goal in diabetes treatment is to re-establish metabolically regulated insulin secretion. Pancreatic beta cell replacement can serve as a means for metabolically regulated insulin delivery. One potentially renewable donor source of pancreatic beta cells needed for replacement therapies could be derived from human pancreatic ductal epithelial cells. Recently, the investigator's have been characterizing two human pancreatic ductule epithelial cell lines (HPDE-7 and HPDE-11 cells) transformed by expression of E6 and E7 gene of the human papilloma virus. Preliminary studies show that these cells form pancreatic ductule-like structures and express ductal cell genes when cultured on Matrigel. Importantly, when the ductule-like structures are cultured in hepatocyte growth factor and nicotinamide the cells synthesize and secrete insulin. Overall the investigators' studies suggest that HPDE cells are pluripotent cells capable of differentiating into either ductal cells or endocrine cells. The investigators' three specific aims are to: (1) characterize the defect that mitogens, differentiation agents, and extracellular matrix have on proliferation and differentiation of HPDE-7 and HPDE-11 cells in vitro; (2) examine whether transplantation of HPDE cells into different anatomical sites within alloxan-induced diabetic athymic mice has an effect on proliferation and differentiation of HPDE cells; (3) examine whether expression of transcription factors involved in beta cell development and maintenance can regulate HPDE cell proliferation and differentiation. Successful completion of these aims will develop a model for studying human beta cell neogenesis from pancreatic duct epithelial cells and may provide methods needed to generate a renewable source of transplantable human beta cell tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK057173-02
Application #
6178223
Study Section
Special Emphasis Panel (ZRG1-MET (01))
Program Officer
Sato, Sheryl M
Project Start
1999-09-30
Project End
2001-09-29
Budget Start
2000-09-30
Budget End
2001-09-29
Support Year
2
Fiscal Year
2000
Total Cost
$147,787
Indirect Cost
Name
Michigan State University
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Tai, Mei-Hui; Upham, Brad L; Olson, Lawrence Karl et al. (2007) Cigarette smoke components inhibited intercellular communication and differentiation in human pancreatic ductal epithelial cells. Int J Cancer 120:1855-62
Tai, Mei-Hui; Chang, Chia-Cheng; Kiupel, Matti et al. (2005) Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 26:495-502
Linning, Katrina D; Tai, Mei-Hui; Madhukar, Burra V et al. (2004) Redox-mediated enrichment of self-renewing adult human pancreatic cells that possess endocrine differentiation potential. Pancreas 29:e64-76
Tai, Mei-Hui; Olson, L Karl; Madhukar, Burra V et al. (2003) Characterization of gap junctional intercellular communication in immortalized human pancreatic ductal epithelial cells with stem cell characteristics. Pancreas 26:e18-26