Artifactual Insulin Release From Differentiated Embryonic Stem Cells
Open accessAbstract
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.
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Several methods of differentiation of ES cells to hepatic and insulin-producing cells have been described, but determining the precise identity of these cells is problematic due to a lack of suitable markers.
“While several methods of differentiation of ES cells to hepatic and insulin-producing cells have been described, determining the precise identity of these cells is problematic due to a lack of suitable markers [20-23].”
From A systematic screen for genes expressed in definitive endoderm by Serial Analysis of Gene Expression (SAGE) (2007) · cites this paper as [21]
The introduction describes several approaches to deriving insulin-containing cells from ES cells. The discussion explains that overlapping pancreatic and neural gene markers can make the identity of purported β-like cells difficult to establish. The paper does not address hepatic-cell differentiation, and it identifies a problem with marker specificity rather than a general lack of suitable markers (page numbers unavailable in our copy). (LLM, conf=0.87)
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Blyszczuk, P., Asbrand, C., Rozzo, A., Kania, G., St-onge, L., Rupnik, M., & Wobus, A. M. (2004) · The International Journal of Developmental Biology · doi:10.1387/ijdb.041904pb · Cited by 110 · see citing works
Hou, J., Charters, A. M., Lee, S. C., Zhao, Y., Wu, M. K., Jones, S. J., Marra, M. A., & Hoodless, P. A. (2007) · BMC Developmental Biology · doi:10.1186/1471-213x-7-92 · Cited by 56 · see citing works
“While several methods of differentiation of ES cells to hepatic and insulin-producing cells have been described, determining the precise identity of these cells is problematic due to a lack of suitable markers [20-23].”
BackgroundLoebel, D. A. F., & Tam, P. P. L. (2005) · Nature Biotechnology · doi:10.1038/nbt1205-1491 · Cited by 18 · see citing works
- Authors
- Hansson, M., Tonning, A., Frandsen, U., Petri, A., Rajagopal, J., Englund, M. C. O., Heller, R. S., Håkansson, J., Fleckner, J., Sköld, H. N., Melton, D., Semb, H., & Serup, P.
- Affiliations
- Department of Developmental Biology, Hagedorn Research Institute, Gentofte, Denmark
- University of Gothenburg (SE)
- Novo Nordisk (Denmark) (DK)
- Howard Hughes Medical Institute (US)
- Cell Therapeutics Scandinavia, Göteborg, Sweden
- Department of Medical Biochemistry, Göteborg University, Göteborg, Sweden
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-10-01
- Volume
- 53
- Issue
- 10
- Pages
- 2603-2609
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2039508080
- Cited by
- 225
- References
- 0
- Citations by year
- 2025: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 1 · 2016: 7 · 2015: 4 · 2014: 8 · 2013: 14 · 2012: 9
- FWCI
- 29.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Funders
- Sahlgrenska Universitetssjukhuset
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- insulin secretion, embryonic stem cells, C-peptide, proinsulin, apoptosis, necrosis, PI3K inhibitors, insulin-producing cells, beta cell differentiation
- MeSH terms
- Insulin Secretion, Animals, C-Peptide, Cell Differentiation, Glucose, Humans, Insulin, Stem Cells, Artifacts, Apoptosis, Cell Culture Techniques, In Situ Nick-End Labeling, Mice
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