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Cited by 1,843Pancreatic function and diabetesPluripotent Stem Cells ResearchDiabetes and associated disorders

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Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo

Kroon, Evert, Martinson, Laura A, Kadoya, Kuniko, Bang, Anne G, Kelly, Olivia G, Eliazer, Susan, Young, Holly, Richardson, Mike, Smart, Nora G, Cunningham, Justine, Agulnick, Alan D, D'Amour, Kevin A, Carpenter, Melissa K, Baetge, Emmanuel E·2008·Nature Biotechnology
DOI 10.1038/nbt1393
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Abstract

Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human beta-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with approximately 3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional beta-cells, including expression of critical beta-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell-derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells.

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Research works printed but not linked: 43

  1. Lakey, J.R., Mirbolooki, M. & Shapiro, A.M. Current status of clinical islet cell transplantation. Methods Mol. Biol. 333, 47–104 (2006).
  2. Amit, M. et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev. Biol. 227, 271–278 (2000). · DOI
  3. Rosler, E.S. et al. Long-term culture of human embryonic stem cells in feeder-free conditions. Dev. Dyn. 229, 259–274 (2004). · DOI
  4. D'Amour, K.A. et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23, 1534–1541 (2005). · DOI · Paper page
  5. D'Amour, K.A. et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392–1401 (2006). · DOI
  6. Jiang, J. et al. Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25, 1940–1953 (2007). · DOI
  7. Tuch, B.E., Osgerby, K.J. & Turtle, J.R. Reversal of diabetes in hyperglycaemic nude mice by human fetal pancreas. Transplant. Proc. 21, 2665–2666 (1989).
  8. Beattie, G.M., Butler, C. & Hayek, A. Morphology and function of cultured human fetal pancreatic cells transplanted into athymic mice: a longitudinal study. Cell Transplant. 3, 421–425 (1994). · DOI
  9. Hayek, A. & Beattie, G.M. Experimental transplantation of human fetal and adult pancreatic islets. J. Clin. Endocrinol. Metab. 82, 2471–2475 (1997).
  10. Castaing, M. et al. Blood glucose normalization upon transplantation of human embryonic pancreas into beta-cell-deficient SCID mice. Diabetologia 44, 2066–2076 (2001). · DOI
  11. Castaing, M., Duvillie, B., Quemeneur, E., Basmaciogullari, A. & Scharfmann, R. Ex vivo analysis of acinar and endocrine cell development in the human embryonic pancreas. Dev. Dyn. 234, 339–345 (2005). · DOI
  12. Jensen, J. Gene regulatory factors in pancreatic development. Dev. Dyn. 229, 176–200 (2004). · DOI
  13. Zorn, A.M. & Wells, J.M. Molecular basis of vertebrate endoderm development. Int. Rev. Cytol. 259, 49–111 (2007). · DOI
  14. Jorgensen, M.C. et al. An illustrated review of early pancreas development in the mouse. Endocr. Rev. 28, 685–705 (2007). · DOI
  15. Gaber, A.O. et al. Human islet graft function in NOD-SCID mice predicts clinical response in islet transplant recipients. Transplant. Proc. 36, 1108–1110 (2004). · DOI
  16. Cabrera, O. et al. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl. Acad. Sci. USA 103, 2334–2339 (2006). · DOI · Paper page
  17. Guz, Y. et al. Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Development 121, 11–18 (1995). · DOI
  18. Collombat, P. et al. Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. J. Clin. Invest. 117, 961–970 (2007). · DOI
  19. Olbrot, M., Rud, J., Moss, L.G. & Sharma, A. Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc. Natl. Acad. Sci. USA 99, 6737–6742 (2002). · DOI
  20. Matsuoka, T.A. et al. Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol. Cell. Biol. 23, 6049–6062 (2003). · DOI
  21. Matsuoka, T.A. et al. The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc. Natl. Acad. Sci. USA 101, 2930–2933 (2004). · DOI
  22. Nishimura, W. et al. A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev. Biol. 293, 526–539 (2006). · DOI
  23. Artner, I. et al. MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells. Diabetes 55, 297–304 (2006). · DOI
  24. Zhang, C. et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol. Cell. Biol. 25, 4969–4976 (2005). · DOI
  25. Wilson, M.E., Kalamaras, J.A. & German, M.S. Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas. Mech. Dev. 115, 171–176 (2002). · DOI
  26. Klimstra, D.S. in Histology for Pathologists. (ed. S.S. Sternberg) 613–647 (Lippincott-Raven Publishers, Philadelphia; 1997).
  27. Marzban, L. et al. Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death. Diabetes 55, 2192–2201 (2006). · DOI
  28. Okamoto, H. The role of poly(ADP-ribose) synthetase in the development of insulin-dependent diabetes and islet B-cell regeneration. Biomed. Biochim. Acta 44, 15–20 (1985).
  29. Eizirik, D.L. et al. Major species differences between humans and rodents in the susceptibility to pancreatic beta-cell injury. Proc. Natl. Acad. Sci. USA 91, 9253–9256 (1994). · DOI
  30. Hosokawa, M., Dolci, W. & Thorens, B. Differential sensitivity of GLUT1- and GLUT2-expressing beta cells to streptozotocin. Biochem. Biophys. Res. Commun. 289, 1114–1117 (2001). · DOI
  31. Yang, H. & Wright, J.R., Jr. Human beta cells are exceedingly resistant to streptozotocin in vivo. Endocrinology 143, 2491–2495 (2002). · DOI
  32. Hering, B.J. et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. J. Am. Med. Assoc. 293, 830–835 (2005). · DOI
  33. Zertal-Zidani, S., Bounacer, A. & Scharfmann, R. Regulation of pancreatic endocrine cell differentiation by sulphated proteoglycans. Diabetologia 50, 585–595 (2007). · DOI
  34. Attali, M. et al. Control of beta-cell differentiation by the pancreatic mesenchyme. Diabetes 56, 1248–1258 (2007). · DOI
  35. Tulachan, S.S. et al. All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas. Diabetes 52, 76–84 (2003). · DOI
  36. Kobayashi, H. et al. Retinoid signaling controls mouse pancreatic exocrine lineage selection through epithelial-mesenchymal interactions. Gastroenterology 123, 1331–1340 (2002). · DOI
  37. Tuch, B.E. & Monk, R.S. Regulation of blood glucose to human levels by human fetal pancreatic xenografts. Transplantation 51, 1156–1160 (1991). · DOI
  38. Tuch, B.E., Jones, A. & Turtle, J.R. Maturation of the response of human fetal pancreatic explants to glucose. Diabetologia 28, 28–31 (1985). · DOI
  39. Tuch, B.E. Reversal of diabetes by human fetal pancreas. Optimization of requirements in the hyperglycemic nude mouse. Transplantation 51, 557–562 (1991). · DOI
  40. Fornoni, A. et al. Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation. Diabetologia 51, 298–308 (2008). · DOI
  41. Weitgasser, R., Davalli, A.M. & Weir, G.C. Measurement of glucose concentrations in rats: differences between glucose meter and plasma laboratory results. Diabetologia 42, 256 (1999). · DOI
  42. Joannides, A. et al. Automated mechanical passaging: a novel and efficient method for human embryonic stem cell expansion. Stem Cells 24, 230–235 (2006). · DOI
  43. Schrot, R.J., Patel, K.T. & Foulis, P. Evaluation of inaccuracies in the measurement of glycemia in the laboratory, by glucose meters, and through measurement of hemoglobin A1c. Clin Diabetes 25, 43–49 (2007). · DOI

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Metadata

Authors
Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., Agulnick, A. D., D'Amour, K. A., Carpenter, M. K., & Baetge, E. E.
ORCID
Venue
Nature Biotechnology
Publisher
Springer Science and Business Media LLC
Published
2008-02-20
Volume
26
Issue
4
Pages
443-452
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
DOI
10.1038/nbt1393
OpenAlex
W2106219965
Cited by
1,843
References
0
Citations by year
2026: 26 · 2025: 44 · 2024: 46 · 2023: 88 · 2022: 67 · 2021: 81 · 2020: 85 · 2019: 76 · 2018: 87 · 2017: 98 · 2016: 122 · 2015: 116 · 2014: 156 · 2013: 168 · 2012: 154
FWCI
150.73
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Biotechnology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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
human embryonic stem cells, beta cell differentiation, glucose-dependent insulin secretion, islet transplantation, diabetes cell therapy, C-peptide, proinsulin processing, streptozotocin-induced hyperglycemia
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Endoderm, Glucose, Humans, Insulin, Cell Culture Techniques, Pancreas, Artificial, Tissue Engineering, Cell Proliferation, Insulin-Secreting Cells, Mice, Embryonic Stem Cells

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