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.
OBJECTIVE
In the adult pancreas, pre-existing beta cells, stem cells, and endocrine progenitor cells residing in the duct lining are considered important sources for beta-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 beta-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 beta cells was significantly increased. beta-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 beta cells but also leads to beta-cell differentiation from duct cells, and the resulting increase in beta-cell mass improves glucose tolerance.
Kozawa
Junji
J
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
Tokui
Yae
Y
Moriwaki
Makoto
M
Li
Ming
M
Ohmoto
Hiroshi
H
Yuan
Ming
M
Zhang
Jun
J
Iwahashi
Hiromi
H
Imagawa
Akihisa
A
Yamagata
Kazuya
K
Tochino
Yoshihiro
Y
Shimomura
Iichiro
I
Higashiyama
Shigeki
S
Miyagawa
Jun-ichiro
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001835:Body Weight; D001973:Bromodeoxyuridine / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D004815:Epidermal Growth Factor / Q000032:analysis / Q000235:genetics*; D015316:Genetic Therapy; D005951:Glucose Tolerance Test; D066257:Heparin-binding EGF-like Growth Factor; D018398:Homeodomain Proteins / Q000032:analysis; D007150:Immunohistochemistry; D007267:Injections; D036341:Intercellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010183:Pancreatic Ducts / Q000737:chemistry; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000032:analysis
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004815:Epidermal Growth Factor; D001973:Bromodeoxyuridine