Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia.
OBJECTIVE
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is expressed in both normal pancreatic islets and in pancreatic cancers, but its role in pancreatic physiology and disease is not known. This report examines the effects of HB-EGF overexpression in mouse pancreas.


METHODS
Transgenic mice were established using a tissue-specific promoter to express an HB-EGF complementary DNA in pancreatic beta cells, effectively elevating HB-EGF protein 3-fold over endogenous levels.


RESULTS
Mice overexpressing HB-EGF in pancreatic islets showed both endocrine and exocrine pancreatic defects. Initially, islets from transgenic mice failed to segregate alpha, beta, delta, and PP cells appropriately within islets, and had impaired separation from ducts and acini. Increased stroma was detected within transgenic islets, expanding with age to cause fibrosis of both endocrine and exocrine compartments. In addition to these structural abnormalities, subsets of transgenic mice developed profound hyperglycemia and/or proliferation of metaplastic ductal epithelium. Both conditions were associated with severe stromal expansion, suggesting a role for islet/stromal interaction in the onset of the pancreatic disease initiated by HB-EGF. Supporting this conclusion, primary mouse fibroblasts adhered to transgenic islets when the 2 tissues were cocultured in vitro, but did not interact with nontransgenic islets.


CONCLUSIONS
An elevation in HB-EGF protein in pancreatic islets led to altered interactions among islet cells and among islets, stromal tissues, and ductal epithelium. Many of the observed phenotypes appeared to involve altered cell adhesion. These data support a role for islet factors in the development of both endocrine and exocrine disease.
Means
Anna L
AL
Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. anna.means@vanderbilt.edu
Ray
Kevin C
KC
Singh
Amar B
AB
Washington
M Kay
MK
Whitehead
Robert H
RH
Harris
Raymond C
RC
Wright
Christopher V E
CV
Coffey
Robert J
RJ
Leach
Steven D
SD
D000818:Animals; D002450:Cell Communication / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004815:Epidermal Growth Factor / Q000235:genetics*; D004847:Epithelial Cells / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000473:pathology* / Q000502:physiology*; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D010182:Pancreatic Diseases / Q000473:pathology* / Q000503:physiopathology*; D010183:Pancreatic Ducts / Q000473:pathology; D010641:Phenotype
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D004815:Epidermal Growth Factor