Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3

doi:10.1083/jcb.200203074

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Published 28 October 2002. doi:10.1083/jcb.200203074

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© The Rockefeller University Press, 0021-9525/2002/10/303 $5.00
The Journal of Cell Biology, Volume 159, Number 2, 303-312

Article

Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3

Yves Heremans¹, Mark Van De Casteele¹, Peter in't Veld¹, Gerard Gradwohl², Palle Serup³, Ole Madsen³, Daniel Pipeleers¹ and Harry Heimberg¹

¹ Diabetes Research Center, Brussels Free University (VUB), B-1090 Brussels, Belgium
² Institut National de la Santé et de la Recherche Médicale, U381, Development and Pathology of the Digestive System, F-67200 Strasbourg, France
³ Hagedorn Research Institute, DK-2820 Gentofte, Denmark

Address correspondence to Harry Heimberg, Diabetes Research Center, Brussels Free University (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium. Tel.: 32-2-477-4548. Fax: 32-2-477-4545. E-mail: hheimber{at}vub.vub.ac.be

Regulatory proteins have been identified in embryonic developmentof the endocrine pancreas. It is unknown whether these factorscan also play a role in the formation of pancreatic endocrinecells from postnatal nonendocrine cells. The present study demonstratesthat adult human pancreatic duct cells can be converted intoinsulin-expressing cells after ectopic, adenovirus-mediatedexpression of the class B basic helix-loop-helix factor neurogenin3 (ngn3), which is a critical factor in embryogenesis of themouse endocrine pancreas. Infection with adenovirus ngn3 (Adngn3)induced gene and/or protein expression of NeuroD/ß2,Pax4, Nkx2.2, Pax6, and Nkx6.1, all known to be essential forß-cell differentiation in mouse embryos. Expressionof ngn3 in adult human duct cells induced Notch ligands Dll1and Dll4 and neuroendocrine- and ß-cell–specificmarkers: it increased the percentage of synaptophysin- and insulin-positivecells 15-fold in ngn3-infected versus control cells. Infectionwith NeuroD/ß2 (a downstream target of ngn3) inducedsimilar effects. These data indicate that the Delta-Notch pathway,which controls embryonic development of the mouse endocrinepancreas, can also operate in adult human duct cells drivingthem to a neuroendocrine phenotype with the formation of insulin-expressingcells.

Key Words: neurogenin 3; islets of langerhans; transdifferentiation; insulin; diabetes mellitus

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