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Originally published in Science Express on 26 April 2001
Science 18 May 2001:
Vol. 292. no. 5520, pp. 1389 - 1394
DOI: 10.1126/science.1058866
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Reports

Differentiation of Embryonic Stem Cells to Insulin-Secreting Structures Similar to Pancreatic Islets

Nadya Lumelsky,1 Olivier Blondel,13 Pascal Laeng,24 Ivan Velasco,1 Rea Ravin,1 Ron McKay1*

Although the source of embryonic stem (ES) cells presents ethical concerns, their use may lead to many clinical benefits if differentiated cell types can be derived from them and used to assemble functional organs. In pancreas, insulin is produced and secreted by specialized structures, islets of Langerhans. Diabetes, which affects 16 million people in the United States, results from abnormal function of pancreatic islets. We have generated cells expressing insulin and other pancreatic endocrine hormones from mouse ES cells. The cells self-assemble to form three-dimensional clusters similar in topology to normal pancreatic islets where pancreatic cell types are in close association with neurons. Glucose triggers insulin release from these cell clusters by mechanisms similar to those employed in vivo. When injected into diabetic mice, the insulin-producing cells undergo rapid vascularization and maintain a clustered, islet-like organization.

1 Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health,
2 Laboratory of System Neuroscience, National Institute of Mental Health, NIH, Bethesda, MD 20892-4092, USA.
3 Human Genome Sciences, Rockville, MD 20850, USA.
4 Psychiatric Genomics, Rockville, MD 20852, USA.
*   To whom correspondence should be addressed. E-mail: mckay{at}codon.nih.gov

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Am J Physiol Endocrinol Metab 284, E177-E183
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Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells.
Y. Hori, I. C. Rulifson, B. C. Tsai, J. J. Heit, J. D. Cahoy, and S. K. Kim (2002)
PNAS 99, 16105-16110
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Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3.
Y. Heremans, M. Van De Casteele, P. in't Veld, G. Gradwohl, P. Serup, O. Madsen, D. Pipeleers, and H. Heimberg (2002)
J. Cell Biol. 159, 303-312
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Cloning and Characterization of Ehox, a Novel Homeobox Gene Essential for Embryonic Stem Cell Differentiation.
M. Jackson, J. W. Baird, N. Cambray, J. D. Ansell, L. M. Forrester, and G. J. Graham (2002)
J. Biol. Chem. 277, 38683-38692
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Normal timing of oligodendrocyte development from genetically engineered, lineage-selectable mouse ES cells.
N. Billon, C. Jolicoeur, Q. L. Ying, A. Smith, and M. Raff (2002)
J. Cell Sci. 115, 3657-3665
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Insulinotropic Hormone Glucagon-Like Peptide-1 Differentiation of Human Pancreatic Islet-Derived Progenitor Cells into Insulin-Producing Cells.
E. J. Abraham, C. A. Leech, J. C. Lin, H. Zulewski, and J. F. Habener (2002)
Endocrinology 143, 3152-3161
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Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complex.
M. Tomioka, M. Nishimoto, S. Miyagi, T. Katayanagi, N. Fukui, H. Niwa, M. Muramatsu, and A. Okuda (2002)
Nucleic Acids Res. 30, 3202-3213
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Cross signaling, cell specificity, and physiology.
J. E. Dumont, S. Dremier, I. Pirson, and C. Maenhaut (2002)
Am J Physiol Cell Physiol 283, C2-C28
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In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells.
L. Yang, S. Li, H. Hatch, K. Ahrens, J. G. Cornelius, B. E. Petersen, and A. B. Peck (2002)
PNAS 99, 8078-8083
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