Overexpression of Heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia

Anna L. Means, Kevin C. Ray, Amar B. Singh, M. Kay Washington, Robert H. Whitehead, Raymond C. Harris, Christopher V.E. Wright, Robert J. Coffey, Steven D. Leach

Research output: Contribution to journalArticle

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Abstract

Background & Aims: 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 over-expression in mouse pancreas. Methods: Transgenic mice were established using a tissue-specific promoter to express an HB-EGF complementary DNA in pancreatic β 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 α, β, δ, 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.

Original languageEnglish (US)
Pages (from-to)1020-1036
Number of pages17
JournalGastroenterology
Volume124
Issue number4
DOIs
StatePublished - Apr 1 2003

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Metaplasia
Epidermal Growth Factor
Heparin
Pancreas
Intercellular Signaling Peptides and Proteins
Fibrosis
Islets of Langerhans
Transgenic Mice
Pancreatic Diseases
Epithelium
Endocrine System Diseases
Mouse Hbegf protein
Pancreatic Neoplasms
Cell Adhesion
Hyperglycemia
Proteins
Complementary DNA
Fibroblasts
Phenotype

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Means, A. L., Ray, K. C., Singh, A. B., Washington, M. K., Whitehead, R. H., Harris, R. C., ... Leach, S. D. (2003). Overexpression of Heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology, 124(4), 1020-1036. https://doi.org/10.1053/gast.2003.50150

Overexpression of Heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. / Means, Anna L.; Ray, Kevin C.; Singh, Amar B.; Washington, M. Kay; Whitehead, Robert H.; Harris, Raymond C.; Wright, Christopher V.E.; Coffey, Robert J.; Leach, Steven D.

In: Gastroenterology, Vol. 124, No. 4, 01.04.2003, p. 1020-1036.

Research output: Contribution to journalArticle

Means, AL, Ray, KC, Singh, AB, Washington, MK, Whitehead, RH, Harris, RC, Wright, CVE, Coffey, RJ & Leach, SD 2003, 'Overexpression of Heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia', Gastroenterology, vol. 124, no. 4, pp. 1020-1036. https://doi.org/10.1053/gast.2003.50150
Means, Anna L. ; Ray, Kevin C. ; Singh, Amar B. ; Washington, M. Kay ; Whitehead, Robert H. ; Harris, Raymond C. ; Wright, Christopher V.E. ; Coffey, Robert J. ; Leach, Steven D. / Overexpression of Heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. In: Gastroenterology. 2003 ; Vol. 124, No. 4. pp. 1020-1036.
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AU - Whitehead, Robert H.

AU - Harris, Raymond C.

AU - Wright, Christopher V.E.

AU - Coffey, Robert J.

AU - Leach, Steven D.

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