Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis intransgenic mice overexpressing transforming growth factor alpha

Background & Aims: The progenitor cells responsible for transforming growth factor (TGF)-alpha-induced pancreatic ductal metaplasia and neoplasia rema in uncharacterized. During pancreatic development, differentiated cell type s arise from ductal progenitor cells expressing the Pdx1 homeodomain transc ription factor. The aims of this study were, first, to evaluate the role of Pdx1-expressing stem cells in MT-TGF alpha transgenic mice, and second, to further characterize cell proliferation and differentiation in this model, Methods: To assess Pdx1 gene expression in normal and metaplastic epitheli um, we performed in vivo reporter gene analysis using heterozygous Pdx1(lac Z/+) and bigenic Pdx1(lacZ/+)/MT-TGF alpha mice. Results: Pdx1(lacZ/+)/MT-T GF alpha bigenics showed up-regulated Pdx1 expression in premalignant metap lastic ductal epithelium. In addition to Pdx1 gene activation, TGF-alpha-in duced metaplastic epithelium demonstrated a pluripotent differentiation cap acity, as evidenced by focal expression of Pax6 and initiation of islet cel l neogenesis. The majority of Pdx1-positive epithelial cells showed no expr ession of insulin, similar to the pattern observed during embryonic develop ment. Conclusions: Overexpression of TGF-alpha induces expansion of a Pdx1- expressing epithelium characterized by focal expression of Pax6 and initiat ion of islet neogenesis, These findings suggest that premalignant events in duced by TGF-alpha in mouse pancreas may recapitulate a developmental progr am active during embryogenesis.