(Journal Article): Insulin production by human embryonic stem cells.
 
Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M (Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, and. Rambam Medical Center, Bat-Galim, Haifa, Israel.)
 
IN: Diabetes 2001; 50(8):1691-1697
Impact Factor(s) of Diabetes: 8.848 (2004), 8.298 (2003), 8.256 (2002), 7.7 (2001)

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ABSTRACT: Type 1 diabetes generally results from autoimmune destruction of pancreatic islet beta-cells, with consequent absolute insulin deficiency and complete dependence on exogenous insulin treatment. The relative paucity of donations for pancreas or islet allograft transplantation has prompted the search for alternative sources for beta-cell replacement therapy. In the current study, we used pluripotent undifferentiated human embryonic stem (hES) cells as a model system for lineage-specific differentiation. Using hES cells in both adherent and suspension culture conditions, we observed spontaneous in vitro differentiation that included the generation of cells with characteristics of insulin-producing beta-cells. Immunohistochemical staining for insulin was observed in a surprisingly high percentage of cells. Secretion of insulin into the medium was observed in a differentiation-dependent manner and was associated with the appearance of other beta-cell markers. These findings validate the hES cell model system as a potential basis for enrichment of human beta-cells or their precursors, as a possible future source for cell replacement therapy in diabetes.

TYPE OF PUBLICATION: Original article

REFERENCES:

  1. The Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993. 329:977-986. [DOD]
  2. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998. 339:69-75. [DOD]
  3. Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000. 343:230-238. [DOD]
  4. Samstein B, Platt JL. Physiologic and immunologic hurdles to xenotransplantation. J Am Soc Nephrol 2001. 12:182-193. [DOD]
  5. Efrat S. Prospects for gene therapy of insulin-dependent diabetes mellitus. Diabetologia 1998. 41:1401-1409. [DOD]
  6. Efrat S. Genetically engineered pancreatic beta-cell lines for cell therapy of diabetes. Ann N Y Acad Sci 1999. 875:286-293. [DOD]
  7. Soria B, Andreu E, Berna G, Fuentes E, Gil A, Leon-Quinto T, Martin F, Montaya E, Nadal A, Reig JA, Ripoll C, Roche E, Sanches-Andres J. Engineering pancreatic islets. Pflugers Arch-Eur J Physiol 2000. 440:1-18. [DOD]
  8. Cheung AT, Dayanandan B, Lewis JT, Korbutt GS, Rajotte RV, Bryer-Ash M, Boylan MO, Wolfe MM, Kieffer TJ. Glucose-dependent insulin release from genetically engineered K cells. Science 2000. 290:1959-1962. [DOD]
  9. Lee HC, Kim SJ, Kim KS, Shin HC, Yoon JW. Remission in models of type 1 diabetes by gene therapy using a single chain insulin-analogue. Nature 2000. 408:483-488. [DOD]
  10. Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, Barshack I, Seijffers R, Kopolovic J, Kaiser N, Karasik A. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 2000. 6:568-572. [DOD]
  11. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshal VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science 1998. 282:1145-1147.
  12. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotech 2000. 18:399-404. [DOD]
  13. Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, Blumenthal PD, Huggins GR, Gearhart JD. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci U S A 1998. 95:13726-13731. [DOD]
  14. Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 2000. 49:157-162. [DOD]
  15. Shamblott MJ, Axelman J, Littlefield JW, Blumenthal PD, Huggins GR, Cui Y, Cheng L, Gearhart JD. Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro. Proc Natl Acad Sci U S A 2001. 98:113-118. [DOD]
  16. Schuldiner M, Yanuka O, Itskovitz-Eldor J, Melton DA, Benvenisty N. Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 2000. 97:11307-11312. [DOD]
  17. Robertson EG (Ed. ): Teratocarcinomas and Embryonic Stem Cells. a practical approach. Washington, D.C., IRL Press 1987. 71-112.
  18. Keller GM. In vitro differentiation of embryonic stem cells. Curr Op Cell Biol 1995. 7:862-869. [DOD]
  19. Itskovitz-Eldor J, Schuldiner M, Karsenti D, Eden A, Yanuka O, Amit M, Soreq H, Benvenisty N. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med 2000. 6:88-95. [DOD]
  20. Green J, Maor G. Effect of metabolic acidosis on the growth hormone/IGF endocrine axis in skeletal growth centers. Kidney Int 2000. 57:2258-2267. [DOD]
  21. Seino Y, Yamamoto T, Inoue K, Imamura M, Kadowaki S, Kojima H, Fujikawa J, Imura H. Abnormal facilitative glucose transporter gene expression in human islet cell tumors. J Clin Endocrinol Metab 1993. 76:75-78. [DOD]
  22. Koranyi LI, Tanizawa Y, Welling CM, Rabin DU, Permutt MA. Human islet glucokinase gene: isolation and sequence analysis of full-length cDNA. Diabetes 1992. 41:807-811 [DOD]
  23. Van Eijk Mj, Van Rooijen MA, Modina S, Scesi L, Folkers G, Van Tol HT, Bevers MM, Fisher SR, Lewin HA, Rakacolli D, Galli C, de Vaureix C, Trounson Ao, Mummery CL, Gandolfi F. Molecular cloning, genetic mapping and developmental expression of bovine POU5F1. Biol Reprod 1999. 60:1093-1103. [DOD]
  24. Tzukerman M, Shachaf C, Ravel Y, Braunstein I, Cohen-Barak O, Yalon-Hacohen M, Skorecki KL. Identification of a novel transcription factor binding element involved in the regulation by differentiation of the human telomerase (hTERT) promoter. Mol Biol Cell 2000. 11:4381-4391. [DOD]
  25. Yeom YI, Fuhrmann G, Ovitt CE, Brehm A, Kazuyuki O, Gross M, Hubner K, Scholer HR. Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 1996. 122:881-894. [DOD]
  26. Niwa H, Miyazaki JI, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 2000. 24:372-376. [DOD]
  27. Edlund H. Transcribing pancreas. Diabetes 1998. 47:1817-1823. [DOD]
  28. Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendhal U, Edlund H. Notch signalling controls pancreatic cell differentiation. Nature 1999. 400:877-881. [DOD]
  29. Schwitzgebel VM, Scheel DW, Conners JR, Kalamaras J, Lee JE, Anderson DJ, Sussel L, Johnson JD, German MS. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 2000. 127:3533-3542. [DOD]
  30. Herrera PL. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 2000. 127:2317-2322. [DOD]
  31. Scharfmann R. Control of early development of the pancreas in rodents and humans: implications of signals from the mesenchyme. Diabetologia 2000. 43:1083-1092. [DOD]
  32. Edlund H. Pancreas: how to get there from the gut? Curr Op Cell Biol 1999. 11:663-668. [DOD]
  33. Kim SK, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev 2001. 15:111-127. [DOD]
  34. Efrat S. Making sense of glucose sensing. Nat Genet 1997. 17:249-250. [DOD]
  35. Matschinsky FM, Glaser B, Magnuson MA. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 1998. 47:307-315. [DOD]
  36. Shepherd PR, Kahn BB. Mechanism of disease: glucose transporters and insulin action: implication for insulin resistance and diabetes mellitus. N Engl J Med 1999. 341:248-257. [DOD]
  37. Alarcon C, Serna J, Perez-Villamil B, de Pablo F. Synthesis and differentially regulated processing of proinsulin in developing chick pancreas, liver and neuroretina. FEBS 1998. 436:361-366. [DOD]
  38. Ling Z, Pipeleers DG. Prolonged exposure of human beta cells to elevated glucose levels results in sustained cellular activation leading to a loss of glucose regulation. J Clin Invest 1996. 98:2805-2812. [DOD]
  39. Jonkers FC, Jonas JC, Gilon P, Henquin JC. Influence of cell number on the characteristics and synchrony of Ca2+ oscillations in clusters of mouse pancreatic islet cells. J Physiol 1999. 520:839-849. [DOD]
  40. Charollais A, Gjinovci A, Huarte J, Bauquis J, Nadal A, Martin F, Andreu E, Sanches-Andres J, Calabrese A, Bosco D, Soria B, Wolheim CB, Herrera PL, Meda P. Junctional communication of pancreatic beta cells contributes to the control of insulin secretion and glucose tolerance. J Clin Invest 2000. 106:235-243. [DOD]
  41. Bonner-Weir S, Taneja M, Weir GC, Tatarkiewics K, Song KH, Sharma A, O'Neil JJ. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci U S A 2000. 97:7999-8004. [DOD]
  42. Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG. Reversal of insulin-dependent diabetes using islet cells generated in vitro from pancreatic stem cells. Nat Med 2000. 6:278-282. [DOD]
  43. Amit M, Carpenter MK, Inokuma MS, Chiu CP, Harris CP, Waknitz MA, Itskovitz-Eldor J, Thomson JA. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol 2000. 227:271-278. [DOD]
  44. Klug MG, Soonpaa MH, Koh GY, Field LJ. Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J Clin Inv 1996. 98:216-224. [DOD]
  45. Hart AW, Baeza N, Apelqvist A, Edlund H. Attenuation of FGF signaling in mouse beta-cells leads to diabetes. Nature 2000. 408:864-868. [DOD]
  46. Halvorsen TL, Beattie GM, Lopez AD, Hayek A, Levine F. Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro. J Endocrinol 2000. 166:103-109. [DOD]

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