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Diabetes 53:2603-2609, 2004
© 2004 by the American Diabetes Association, Inc.

Artifactual Insulin Release From Differentiated Embryonic Stem Cells

Mattias Hansson1, Anna Tonning2, Ulrik Frandsen1, Andreas Petri1,3, Jayaraj Rajagopal4, Mikael C.O. Englund5, R. Scott Heller1, Joakim Håkansson2, Jan Fleckner3, Helen Nilsson Sköld2, Douglas Melton4, Henrik Semb2, and Palle Serup1

1 Department of Developmental Biology, Hagedorn Research Institute, Gentofte, Denmark
2 Department of Medical Biochemistry, Göteborg University, Göteborg, Sweden
3 Department of Molecular Genetics, Novo Nordisk A/S, Bagsvaerd, Denmark
4 Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts
5 Cell Therapeutics Scandinavia, Göteborg, Sweden

Several recent reports claim the generation of insulin-producing cells from embryonic stem cells via the differentiation of progenitors that express nestin. Here, we investigate further the properties of these insulin-containing cells. We find that although differentiated cells contain immunoreactive insulin, they do not contain proinsulin-derived C-peptide. Furthermore, we find variable insulin release from these cells upon glucose addition, but C-peptide release is never detected. In addition, many of the insulin-immunoreactive cells are undergoing apoptosis or necrosis. We further show that cells cultured in the presence of a phosphoinositide 3-kinase inhibitor, which previously was reported to facilitate the differentiation of insulin+ cells, are not C-peptide immunoreactive but take up fluorescein isothiocyanate–labeled insulin from the culture medium. Together, these data suggest that nestin+ progenitor cells give rise to a population of cells that contain insulin, not as a result of biosynthesis but from the uptake of exogenous insulin. We conclude that C-peptide biosynthesis and secretion should be demonstrated to claim insulin production from embryonic stem cell progeny.

Address correspondence and reprint requests to Palle Serup, Ph.D., Department of Developmental Biology, Hagedorn Research Institute, Niels Steensens vej 6, DK-2820 Gentofte, Denmark. E-mail: pas{at}hagedorn.dk. Or to Henrik Semb, Section for Endocrinology, Lunds University, Lund, Sweden. E-mail: henrik.semb{at}endo.mas.lu.se


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