Gastroenterology

Gastroenterology

Volume 117, Issue 6, December 1999, Pages 1416-1426
Gastroenterology

Liver, Pancreas, and Biliary Tract
Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor α,☆☆

https://doi.org/10.1016/S0016-5085(99)70292-1Get rights and content

Abstract

Background & Aims: The progenitor cells responsible for transforming growth factor (TGF)-α–induced pancreatic ductal metaplasia and neoplasia remain uncharacterized. During pancreatic development, differentiated cell types arise from ductal progenitor cells expressing the Pdx1 homeodomain transcription factor. The aims of this study were, first, to evaluate the role of Pdx1-expressing stem cells in MT-TGFα transgenic mice, and second, to further characterize cell proliferation and differentiation in this model. Methods: To assess Pdx1 gene expression in normal and metaplastic epithelium, we performed in vivo reporter gene analysis using heterozygous Pdx1lacZ/+ and bigenic Pdx1lacZ/+/MT-TGFα mice. Results: Pdx1lacZ/+/MT-TGFα bigenics showed up-regulated Pdx1 expression in premalignant metaplastic ductal epithelium. In addition to Pdx1 gene activation, TGF-α–induced metaplastic epithelium demonstrated a pluripotent differentiation capacity, as evidenced by focal expression of Pax6 and initiation of islet cell neogenesis. The majority of Pdx1-positive epithelial cells showed no expression of insulin, similar to the pattern observed during embryonic development. Conclusions: Overexpression of TGF-α induces expansion of a Pdx1-expressing epithelium characterized by focal expression of Pax6 and initiation of islet neogenesis. These findings suggest that premalignant events induced by TGF-α in mouse pancreas may recapitulate a developmental program active during embryogenesis.

GASTROENTEROLOGY 1999;117:1416-1426

Section snippets

Transgenic mouse breeding and tissue harvest

The MT-TGFα transgenic mouse line 1745-815 was propagated by crossing transgenic males with C57BL/6 × DBA females. Resulting litters were screened by polymerase chain reaction (PCR) analysis of genomic tail DNA. Transgenic offspring were identified by amplification of a 260–base pair PCR product using the primers GAGACAGTGGTCTGAAGATCC and ACAGGTTGTCTTCCAAACTGG.19 Transgenic mice of both sexes were studied at various ages after induction of TGF-α expression. Age-matched nontransgenic littermates

Ductal metaplasia develops progressively in MT-TGFα mice

As reported previously,14, 15 pancreatic tissue from MT-TGFα transgenic mice showed uniform pancreatic fibrosis and multiple foci of metaplastic ductal epithelium (Figure 1A–D).

. Serial development of pancreatic pseudoductular metaplasia and early hyperplasia in MT-TGFα mice. (A) Normal histological appearance of nontransgenic mouse pancreas, showing a preponderance of acinar cells with scattered islet tissue (*). (B) Representative section from pancreas of an MT-TGFα mouse 4 weeks after weaning

Discussion

This study shows enhanced cellular proliferation and widespread activation of the Pdx1 homeobox gene within TGF-α–induced metaplastic ductal epithelium. In addition, this metaplastic epithelium exhibited a pluripotent differentiation capacity, as evidenced by the ability to generate both islet and ductal elements. Together, these findings suggest that TGF-α overexpression results in expansion of a metaplastic epithelium displaying features in common with the embryonic pancreas. These

Acknowledgements

The authors thank Dr. Graham Dockray for generously providing the rabbit anti–chromogranin A antibody and Dr. Randall Reed for generously providing rabbit anti-Pax6 antiserum; Drs. Roland Stein, Mark Magnuson, and Anna Means for helpful discussions; and Liying Yang for expert technical assistance.

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    Address requests for reprints to: Steven D. Leach, M.D., Division of Surgical Oncology, Vanderbilt University Medical Center, T-2104 Medical Center North, 21st and Garland Streets, Nashville, Tennessee 37232-2736. e-mail: [email protected]; fax: (615) 343-2030.

    ☆☆

    Supported by National Institutes of Health (NIH) grant DK56211 (to S.D.L.), NIH grant DK42502 (to C.V.E.W.), Juvenile Diabetes Foundation Fellowship no. 397019 (to M.G.), NIH F32 CA79107 (to C.R.S.), NIH F32 CA76698 (to I.M.M.), NIH grant P30 AAR 41943 (core services), NIH grant CA68485 (Vanderbilt-Ingram Cancer Center), and a Department of Veterans Affairs Merit Review (to J.R.G.).

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