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Diabetes 52:2016-2024, 2003
© 2003 by the American Diabetes Association, Inc.

Pancreatic Precursors and Differentiated Islet Cell Types From Murine Embryonic Stem Cells

An In Vitro Model to Study Islet Differentiation

Brenda W. Kahan1,2, Lynn M. Jacobson1,2, Debra A. Hullett1, Jaime M. Ochoada1,2, Terry D. Oberley3, Katharine M. Lang1,2, and Jon S. Odorico1,2

1 Department of Surgery, University of Wisconsin-Madison School of Medicine and William S. Middleton Memorial Veterans Administration Hospital, Madison, Wisconsin
2 WiCell Research Institute, Madison, Wisconsin
3 Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and William S. Middleton Memorial Veterans Administration Hospital, Madison, Wisconsin

Embryonic stem (ES) cells differentiating in vitro reproduce many facets of early embryonic development, including the expression of developmentally regulated transcription factors and the differentiation of multipotent precursor cells. ES cells were evaluated for their ability to differentiate into pancreatic and islet lineage-restricted stages including pancreatic duodenal homeobox 1 (PDX1)-positive pancreatic precursor cells, early endocrine cell progenitors, and islet hormone-producing cells. Following growth and differentiation in nonselective medium containing serum, murine ES cells spontaneously differentiated into cells individually expressing each of the four major islet hormones: insulin, glucagon, somatostatin, and pancreatic polypeptide. PDX1 immunostaining cells appeared first, before hormone-positive cells had emerged. Hormone-positive cells appeared within focal clusters of cells coexpressing PDX1 and the nonclassical hormone markers peptide YY (YY) and islet amyloid polypeptide (IAPP) in combination with the definitive hormones, characteristic of endocrine cells appearing during early pancreaticogenesis. This system allows the investigation of many facets of islet development since it promotes the appearance of the complete range of islet phenotypes and reproduces important developmental stages of normal islet cytodifferentiation in differentiating ES cell cultures.

Address correspondence and reprint requests to Jon S. Odorico, University of Wisconsin-Madison School of Medicine, University of Wisconsin Hospital and Clinics, H4/756 Clinical Science Center, 600 Highland Ave., Madison, WI 53792. E-mail: jon{at}tx.surgery.wisc.edu


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