Regenerative and Therapeutic Effects of Heparin-binding Epidermal Growth Factor-like Growth Factor on Diabetes by Gene Transduction Through Retrograde Pancreatic Duct Injection of Adenovirus Vector

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Abstract

Objectives:

In the adult pancreas, pre-existing β cells, stem cells, and endocrine progenitor cells residing in the duct lining are considered important sources for β-cell regeneration. A member of the epidermal growth factor (EGF) family, heparin binding (HB)-EGF, may promote this process. We examined whether HB-EGF gene transduction into duct cells could promote β-cell regeneration.

Methods:

We administered an HB-EGF adenovirus vector construct to male Institute of Cancer Research mice by retrograde injection through the pancreatic duct. We also performed HB-EGF gene transduction into cultured duct cells.

Results:

On immunohistochemical and histomorphometric analysis of the experimental group, insulin-positive cells differentiated from duct cells, and the 5-bromo-2-deoxyuridine labeling index of β cells was significantly increased. β-cell mass was also increased, and the glucose tolerance of diabetic mice was improved at 12 weeks after injection. Using cultured pancreatic duct cells, we confirmed that HB-EGF gene transduction induced both insulin gene expression and insulin production by these cells.

Conclusions:

These results indicate that HB-EGF gene transduction into adult pancreatic duct cells not only promotes the proliferation of pre-existing β cells but also leads to β-cell differentiation from duct cells, and the resulting increase in β-cell mass improves glucose tolerance.

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