Use of Extra-Pancreatic Tissues for Cell Replacement Therapy for Diabetes

  • Irit Meivar-Levy
  • Sarah Ferber


Pancreatic islet transplantation may constitute the best approach for the long-term control of blood glucose levels in the treatment of diabetes. However, tissue replacement therapy will become widely available as a treatment for diabetic patients only when islets or insulin-producing cells are available in unlimited amounts, and will not be rejected by the diabetic recipients. The present chapter will analyze the option of using adult extrapancreatic tissues for regulated insulin production. Two major approaches could endow adult extra-pancreatic tissues with characteristics and functions that can be used for diabetes cell replacement therapy: First, insulin gene therapy, which involves the ectopic expression of constructs encoding the proinsulin gene or modified proinsulin sequences in adult extra-pancreatic cells from different sources. Second, the induction of a process called developmental redirection of extra-pancreatic tissues into insulin-producing cells. The second approach exploits the instructive roles of pancreatic transcription and soluble factors in controlling pancreas organogenesis in the embryo to dictate the induction of pancreatic lineage and function also in adult tissues. This approach endows adult extra-pancreatic tissues with pancreatic characteristics and function, thus promoting ex vivo differentiation into insulinproducing and secreting cells. Using adult extra-pancreatic tissues may result in the generation of custom made “self” surrogate pancreatic beta cells for the treatment of diabetes, bypassing both the shortage in tissue availability from cadaveric donors and the need for life-long immunosuppression.


Beta Cell Pancreatic Beta Cell Insulin Production Insulin Gene Cell Replacement Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Stock PG, Bluestone JA (2004) Beta-cell replacement for type I diabetes. Annu Rev Med 55:133–156PubMedCrossRefGoogle Scholar
  2. 2.
    Meivar-Levy I, Ferber S (2006) Regenerative medicine: using liver to generate pancreas for treating diabetes. Isr Med Assoc J 8:430–434PubMedGoogle Scholar
  3. 3.
    Meivar-Levy I, Ferber S (2003) New organs from our own tissues: liver-to-pancreas transdifferentiation. Trends Endocrinol Metab 14:460–466PubMedCrossRefGoogle Scholar
  4. 4.
    Hayek A (2005) Cell replacement in type 1 diabetes mellitus. J Pediatr Endocrinol Metab 18:1157–1161PubMedGoogle Scholar
  5. 5.
    Samson SL, Chan L (2006) Gene therapy for diabetes: reinventing the islet. Trends Endocrinol Metab 17:92–100PubMedCrossRefGoogle Scholar
  6. 6.
    Thomas MK, Habener JF (2002) Pancreas development. In: Gill RG (ed) Immunologically mediated endocrine diseases. Lippincott Williams & Wilkins, Baltimore, MD, pp 141–424.Google Scholar
  7. 7.
    Soria B, Skoudy A, Martin F (2001) From stem cells to beta cells: new strategies in cell therapy of diabetes mellitus. Diabetologia 44:407–415PubMedCrossRefGoogle Scholar
  8. 8.
    Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394PubMedCrossRefGoogle Scholar
  9. 9.
    Hussain MA, Theise ND (2004) Stem-cell therapy for diabetes mellitus. Lancet 364:203–205PubMedCrossRefGoogle Scholar
  10. 10.
    Berna G, Leon-Quinto T, Ensenat-Waser R, Montanya E, Martin F, Soria B (2001) Stem cells and diabetes. Biomed Pharmacother 55:206–212PubMedCrossRefGoogle Scholar
  11. 11.
    Brivanlou AH, Gage FH, Jaenisch R, Jessell T, Melton D, Rossant J (2003) Stem cells. Setting standards for human embryonic stem cells. Science 300:913–916PubMedCrossRefGoogle Scholar
  12. 12.
    Watt FM, Hogan BL (2000) Out of Eden: stem cells and their niches. Science 287:1427–1430PubMedCrossRefGoogle Scholar
  13. 13.
    Jun HS, Yoon JW (2005) Approaches for the cure of type 1 diabetes by cellular and gene therapy. Curr Gene Ther 5:249–262PubMedCrossRefGoogle Scholar
  14. 14.
    Giannoukakis N, Trucco M (2005) Gene therapy for type 1 diabetes. Am J Ther 12:512–528PubMedCrossRefGoogle Scholar
  15. 15.
    Tessem JS, DeGregori J (2004) Roles for bone-marrow-derived cells in beta-cell maintenance. Trends Mol Med 10:558–564PubMedCrossRefGoogle Scholar
  16. 16.
    Schuit F, Flamez D, De Vos A, Pipeleers D (2002) Glucose-regulated gene expression maintaining the glucose-responsive state of beta cells. Diabetes 51:S326–S332PubMedCrossRefGoogle Scholar
  17. 17.
    Halban PA, Kahn SE, Lernmark A, Rhodes CJ (2001) Gene and cell-replacement therapy in the treatment of type 1 diabetes: how high must the standards be set? Diabetes 50:2181–2191PubMedCrossRefGoogle Scholar
  18. 18.
    Soria B, Andreu E, Berna G, Fuentes E, Gil A, Leon-Quinto T, Martin F, Montanya E, Nadal A, Reig JA, Ripoll C, Roche E, Sanchez-Andres JV, Segura J (2000) Engineering pancreatic islets. Pflugers Arch 440:1–18PubMedGoogle Scholar
  19. 19.
    Geddes BJ, Harding TC, Lightman SL, Uney JB (1999) Assessing viral gene therapy in neuroendocrine models. Front Neuroendocrinol 20:296–316PubMedCrossRefGoogle Scholar
  20. 20.
    Gros L, Riu E, Montoliu L, Ontiveros M, Lebrigand L, Bosch F (1999) Insulin production by engineered muscle cells. Hum Gene Ther 10:1207–1217PubMedCrossRefGoogle Scholar
  21. 21.
    Groskreutz DJ, Sliwkowski MX, Gorman CM (1994) Genetically engineered proinsulin constitutively processed and secreted as mature, active insulin. J Biol Chem 269:6241–6245PubMedGoogle Scholar
  22. 22.
    Simonson GD, Groskreutz DJ, Gorman CM, MacDonald MJ (1996) Synthesis and processing of genetically modified human proinsulin by rat myoblast primary cultures. Hum Gene Ther 7:71–78PubMedCrossRefGoogle Scholar
  23. 23.
    Nett PC, Sollinger HW, Alam T (2003) Hepatic insulin gene therapy in insulindependent diabetes mellitus. Am J Transplant 3:1197–1203PubMedCrossRefGoogle Scholar
  24. 24.
    Dong H, Woo SL (2001) Hepatic insulin production for type 1 diabetes. Trends Endocrinol Metab 12:441–446PubMedCrossRefGoogle Scholar
  25. 25.
    Yoon JW, Jun HS (2002) Recent advances in insulin gene therapy for type 1 diabetes. Trends Mol Med 8:62–68PubMedCrossRefGoogle Scholar
  26. 26.
    Young LS, Searle PF, Onion D, Mautner V (2006) Viral gene therapy strategies: from basic science to clinical application. J Pathol 208:299–318PubMedCrossRefGoogle Scholar
  27. 27.
    Walther W, Stein U (2000) Viral vectors for gene transfer: a review of their use in the treatment of human diseases. Drugs 60:249–271PubMedCrossRefGoogle Scholar
  28. 28.
    Lundstrom K (2003) Latest development in viral vectors for gene therapy. Trends Biotechnol 21:117–122PubMedCrossRefGoogle Scholar
  29. 29.
    Loewen N, Poeschla EM (2005) Lentiviral vectors. Adv Biochem Eng Biotechnol 99:169–191PubMedGoogle Scholar
  30. 30.
    Klimatcheva E, Rosenblatt JD, Planelles V (1999) Lentiviral vectors and gene therapy. Front Biosci 4:D481–D496PubMedCrossRefGoogle Scholar
  31. 31.
    Connolly JB (2002) Lentiviruses in gene therapy clinical research. Gene Ther 9:1730–1734PubMedCrossRefGoogle Scholar
  32. 32.
    Grieger JC, Samulski RJ (2005) Adeno-associated virus as a gene therapy vector: vector development, production and clinical applications. Adv Biochem Eng Biotechnol 99:119–145PubMedGoogle Scholar
  33. 33.
    Vasileva A, Jessberger R (2005) Precise hit: adeno-associated virus in gene targeting. Nat Rev Microbiol 3:837–847PubMedCrossRefGoogle Scholar
  34. 34.
    Hagstrom JE (2003) Plasmid-based gene delivery to target tissues in vivo: the intravascular approach. Curr Opin Mol Ther 5:338–344PubMedGoogle Scholar
  35. 35.
    Liu F, Tyagi P (2005) Naked DNA for liver gene transfer. Adv Genet 54:43–64PubMedGoogle Scholar
  36. 36.
    Wells DJ (2004) Opening the floodgates: clinically applicable hydrodynamic delivery of plasmid DNA to skeletal muscle. Mol Ther 10:207–208PubMedCrossRefGoogle Scholar
  37. 37.
    Roberts JL, Phillips M, Rosa PA, Budarf M, Herbert E (1979) Processing of common precursor forms of adrenocorticotropin and endorphins in cultures of mouse pituitary cells and in mouse pituitary. Prog Clin Biol Res 31:761–777PubMedGoogle Scholar
  38. 38.
    Giagnoni G, Sabol SL, Nirenberg M (1977) Synthesis of opiate peptides by a clonal pituitary tumor cell line. Proc Natl Acad Sci USA 74:2259–2263PubMedCrossRefGoogle Scholar
  39. 39.
    Moore HP, Walker MD, Lee F, Kelly RB (1983) Expressing a human proinsulin cDNA in a mouse ACTH-secreting cell. Intracellular storage, proteolytic processing, and secretion on stimulation. Cell 35:531–538PubMedCrossRefGoogle Scholar
  40. 40.
    Lipes MA, Cooper EM, Skelly R, Rhodes CJ, Boschetti E, Weir GC, et al (1996) Insulinsecreting non-islet cells are resistant to autoimmune destruction. Proc Natl Acad Sci U S A 93:8595–8600PubMedCrossRefGoogle Scholar
  41. 41.
    Wu L, Nicholson W, Wu CY, Xu M, McGaha A, Shiota M, et al (2003) Engineering physiologically regulated insulin secretion in non-beta cells by expressing glucagonlike peptide 1 receptor. Gene Ther 10:1712–1720PubMedCrossRefGoogle Scholar
  42. 42.
    Faradji RN, Havari E, Chen Q, Gray J, Tornheim K, Corkey BE, et al (2001) Glucoseinduced toxicity in insulin-producing pituitary cells that coexpress GLUT2 and glucokinase. Implications for metabolic engineering. J Biol Chem 276:36695–36702. Epub 2001 Jul 6PubMedCrossRefGoogle Scholar
  43. 43.
    Hughes SD, Quaade C, Johnson JH, Ferber S, Newgard CB (1993) Transfection of AtT-20ins cells with GLUT-2 but not GLUT-1 confers glucose-stimulated insulin secretion. Relationship to glucose metabolism. J Biol Chem 268:15205–15212PubMedGoogle Scholar
  44. 44.
    Schnedl WJ, Ferber S, Johnson JH, Newgard CB (1994) STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. Diabetes 43:1326–1333PubMedCrossRefGoogle Scholar
  45. 45.
    Tang SC, Sambanis A (2003) Development of genetically engineered human intestinal cells for regulated insulin secretion using rAAV-mediated gene transfer. Biochem Biophys Res Commun 303:645–652PubMedCrossRefGoogle Scholar
  46. 46.
    Ramshur EB, Rull TR, Wice BM (2002) Novel insulin/GIP co-producing cell lines provide unexpected insights into Gut K-cell function in vivo. J Cell Physiol 192:339–350PubMedCrossRefGoogle Scholar
  47. 47.
    Corbett JA (2001) K cells: a novel target for insulin gene therapy for the prevention of diabetes. Trends Endocrinol Metab 12:140–142PubMedCrossRefGoogle Scholar
  48. 48.
    Cheung AT, Dayanandan B, Lewis JT, Korbutt GS, Rajotte RV, Bryer-Ash M, et al (2000) Glucose-dependent insulin release from genetically engineered K cells. Science 290:1959–1962PubMedCrossRefGoogle Scholar
  49. 49.
    Holst JJ, Orskov C (2001) Incretin hormones—an update. Scand J Clin Lab Invest Suppl 234:75–85PubMedGoogle Scholar
  50. 50.
    Anini Y, Brubaker PL (2003) Muscarinic receptors control glucagon-like peptide 1 secretion by human endocrine L cells. Endocrinology 144:3244–3250PubMedCrossRefGoogle Scholar
  51. 51.
    Sawada M, Dickinson CJ (1997) The G cell. Annu Rev Physiol 59:273–298PubMedCrossRefGoogle Scholar
  52. 52.
    Lu YC, Sternini C, Rozengurt E, Zhukova E (2005) Release of transgenic human insulin from gastric g cells: a novel approach for the amelioration of diabetes. Endocrinology 146:2610–2619PubMedCrossRefGoogle Scholar
  53. 53.
    Rizzuto G, Cappelletti M, Mennuni C, Wiznerowicz M, DeMartis A, Maione D, et al (2000) Gene electrotransfer results in a high-level transduction of rat skeletal muscle and corrects anemia of renal failure. Hum Gene Ther 11:1891–1900PubMedCrossRefGoogle Scholar
  54. 54.
    Osborne WR, Ramesh N, Lau S, Clowes MM, Dale DC, Clowes AW (1995) Gene therapy for long-term expression of erythropoietin in rats. Proc Natl Acad Sci USA 92:8055–8058PubMedCrossRefGoogle Scholar
  55. 55.
    van de Ven WJ, Voorberg J, Fontijn R, Pannekoek H, van den Ouweland AM, van Duijnhoven HL, et al (1990) Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Mol Biol Rep 14:265–275PubMedCrossRefGoogle Scholar
  56. 56.
    Hay CW, Docherty K (2003) Enhanced expression of a furin-cleavable proinsulin. J Mol Endocrinol 31:597–607PubMedCrossRefGoogle Scholar
  57. 57.
    Yasutomi K, Itokawa Y, Asada H, Kishida T, Cui FD, Ohashi S, et al (2003) Intravascular insulin gene delivery as potential therapeutic intervention in diabetes mellitus. Biochem Biophys Res Commun 310:897–903PubMedCrossRefGoogle Scholar
  58. 58.
    Yanagita M, Hoshino H, Nakayama K, Takeuchi T (1993) Processing of mutated proinsulin with tetrabasic cleavage sites to mature insulin reflects the expression of furin in nonendocrine cell lines. Endocrinology 133:639–644PubMedCrossRefGoogle Scholar
  59. 59.
    Abai AM, Hobart PM, Barnhart KM (1999) Insulin delivery with plasmid DNA. Hum Gene Ther 10:2637–2649PubMedCrossRefGoogle Scholar
  60. 60.
    Shaw JA, Delday MI, Hart AW, Docherty HM, Maltin CA, Docherty K (2002) Secretion of bioactive human insulin following plasmid-mediated gene transfer to non-neuroendocrine cell lines, primary cultures and rat skeletal muscle in vivo. J Endocrinol 172:653–672PubMedCrossRefGoogle Scholar
  61. 61.
    Ratanamart J, Shaw JA (2006) Plasmid-mediated muscle-targeted gene therapy for circulating therapeutic protein replacement: a tale of the tortoise and the hare? Curr Gene Ther 6:93–110PubMedCrossRefGoogle Scholar
  62. 62.
    Croze F, Prud’homme GJ (2003) Gene therapy of streptozotocin-induced diabetes by intramuscular delivery of modified preproinsulin genes. J Gene Med 5:425–437PubMedCrossRefGoogle Scholar
  63. 63.
    Kon OL, Sivakumar S, Teoh KL, Lok SH, Long YC (1999) Naked plasmid-mediated gene transfer to skeletal muscle ameliorates diabetes mellitus. J Gene Med 1:186–194PubMedCrossRefGoogle Scholar
  64. 64.
    Martinenghi S, Cusella De Angelis G, Biressi S, Amadio S, Bifari F, Roncarolo MG, et al (2002) Human insulin production and amelioration of diabetes in mice by electrotransfer-enhanced plasmid DNA gene transfer to the skeletal muscle. Gene Ther 9:1429–1437PubMedCrossRefGoogle Scholar
  65. 65.
    Charron MJ, Gorovits N, Laidlaw JS, Ranalletta M, Katz EB (2005) Use of GLUT-4 null mice to study skeletal muscle glucose uptake. Clin Exp Pharmacol Physiol 32:308–313PubMedCrossRefGoogle Scholar
  66. 66.
    Otaegui PJ, Ontiveros M, Ferre T, Riu E, Jimenez R, Bosch F (2002) Glucose-regulated glucose uptake by transplanted muscle cells expressing glucokinase counteracts diabetic hyperglycemia. Hum Gene Ther 13:2125–2133PubMedCrossRefGoogle Scholar
  67. 67.
    Jimenez-Chillaron JC, Telemaque-Potts S, Gomez-Valades AG, Anderson P, Newgard CB, Gomez-Foix AM (2002) Glucokinase gene transfer to skeletal muscle of diabetic Zucker fatty rats improves insulin-sensitive glucose uptake. Metabolism 51:121–126PubMedCrossRefGoogle Scholar
  68. 68.
    Printz RL, Magnuson MA, Granner DK (1993) Mammalian glucokinase. Annu Rev Nutr 13:463–496PubMedCrossRefGoogle Scholar
  69. 69.
    Mas A, Montane J, Anguela XM, Munoz S, Douar AM, Riu E, et al (2006) Reversal of type 1 diabetes by engineering a glucose sensor in skeletal muscle. Diabetes 55:1546–1553PubMedCrossRefGoogle Scholar
  70. 70.
    Gould GW, Holman GD (1993) The glucose transporter family: structure, function and tissue-specific expression. Biochem J 295:329–341PubMedGoogle Scholar
  71. 71.
    Muzzin P, Eisensmith RC, Copeland KC, Woo SL (1997) Hepatic insulin gene expression as treatment for type 1 diabetes mellitus in rats. Mol Endocrinol 11:833–837PubMedCrossRefGoogle Scholar
  72. 72.
    Lee HC, Kim SJ, Kim KS, Shin HC, Yoon JW (2000) Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 408:483–488PubMedCrossRefGoogle Scholar
  73. 73.
    Burkhardt BR, Loiler SA, Anderson JA, Kilberg MS, Crawford JM, Flotte TR, et al (2003) Glucose-responsive expression of the human insulin promoter in HepG2 human hepatoma cells. Ann N Y Acad Sci 1005:237–241PubMedCrossRefGoogle Scholar
  74. 74.
    Streeper RS, Svitek CA, Chapman S, Greenbaum LE, Taub R, O’Brien RM (1997) A multicomponent insulin response sequence mediates a strong repression of mouse glucose-6-phosphatase gene transcription by insulin. J Biol Chem 272:11698–11701PubMedCrossRefGoogle Scholar
  75. 75.
    Chen R, Meseck ML, Woo SL (2001) Auto-regulated hepatic insulin gene expression in type 1 diabetic rats. Mol Ther 3:584–590PubMedCrossRefGoogle Scholar
  76. 76.
    Chen R, Meseck M, McEvoy RC, Woo SL (2000) Glucose-stimulated and self-limiting insulin production by glucose 6-phosphatase promoter driven insulin expression in hepatoma cells. Gene Ther 7:1802–1809PubMedCrossRefGoogle Scholar
  77. 77.
    Doiron B, Cuif MH, Kahn A (1996) Glucose catabolism induces the L-type pyruvate kinase gene (125a). Biochem Soc Trans 24:250SPubMedGoogle Scholar
  78. 78.
    Shih HM, Liu Z, Towle HC (1995) Two CACGTG motifs with proper spacing dictate the carbohydrate regulation of hepatic gene transcription. J Biol Chem 270:21991–21997PubMedCrossRefGoogle Scholar
  79. 79.
    Wanke IE, Wong NC (1999) Hormonal and dietary regulation of a mammalian gene introduced into rat liver by direct injection. Hum Gene Ther 10:1491–1497PubMedCrossRefGoogle Scholar
  80. 80.
    Thule PM, Liu J, Phillips LS (2000) Glucose regulated production of human insulin in rat hepatocytes. Gene Ther 7:205–214PubMedCrossRefGoogle Scholar
  81. 81.
    Thule PM, Liu JM (2000) Regulated hepatic insulin gene therapy of STZ-diabetic rats. Gene Ther 7:1744–1752PubMedCrossRefGoogle Scholar
  82. 82.
    Lu D, Tamemoto H, Shibata H, Saito I, Takeuchi T (1998) Regulatable production of insulin from primary-cultured hepatocytes: insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin. Gene Ther 5:888–895PubMedCrossRefGoogle Scholar
  83. 83.
    Rencurel F, Waeber G, Antoine B, Rocchiccioli F, Maulard P, Girard J, et al (1996) Requirement of glucose metabolism for regulation of glucose transporter type 2 (GLUT2) gene expression in liver. Biochem J 314:903–909PubMedGoogle Scholar
  84. 84.
    Postic C, Burcelin R, Rencurel F, Pegorier JP, Loizeau M, Girard J, et al (1993) Evidence for a transient inhibitory effect of insulin on GLUT2 expression in the liver: studies in vivo and in vitro. Biochem J 293:119–124PubMedGoogle Scholar
  85. 85.
    Asano T, Katagiri H, Tsukuda K, Lin JL, Ishihara H, Yazaki Y, et al (1992) Upregulation of GLUT2 mRNA by glucose, mannose, and fructose in isolated rat hepatocytes. Diabetes 41:22–25PubMedCrossRefGoogle Scholar
  86. 86.
    Kim YD, Park KG, Morishita R, Kaneda Y, Kim SY, Song DK, et al (2006) Liver-directed gene therapy of diabetic rats using an HVJ-E vector containing EBV plasmids expressing insulin and GLUT 2 transporter. Gene Ther 13:216–224PubMedCrossRefGoogle Scholar
  87. 87.
    Auricchio A, Gao GP, Yu QC, Raper S, Rivera VM, Clackson T, et al (2002) Constitutive and regulated expression of processed insulin following in vivo hepatic gene transfer. Gene Ther 9:963–971PubMedCrossRefGoogle Scholar
  88. 88.
    Grafi G (2004) How cells dedifferentiate: a lesson from plants. Dev Biol 268: 1–6PubMedCrossRefGoogle Scholar
  89. 89.
    Slack JM, Tosh D (2001) Transdifferentiation and metaplasia—switching cell types. Curr Opin Genet Dev 11:581–586PubMedCrossRefGoogle Scholar
  90. 90.
    Li WC, Horb ME, Tosh D, Slack JM (2005) In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech Dev 122:835–847PubMedCrossRefGoogle Scholar
  91. 91.
    Pomerantz J, Blau HM (2004) Nuclear reprogramming: a key to stem cell function in regenerative medicine. Nat Cell Biol 6:810–816PubMedCrossRefGoogle Scholar
  92. 92.
    Jonsson J, Carlsson L, Edlund T, Edlund H (1994) Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371:606–609PubMedCrossRefGoogle Scholar
  93. 93.
    Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, et al (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122:983–995PubMedGoogle Scholar
  94. 94.
    Miller CP, McGehee RE, Jr., Habener JF (1994) IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J 13:1145–1156PubMedGoogle Scholar
  95. 95.
    Waeber G, Thompson N, Nicod P, Bonny C (1996) Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor. Mol Endocrinol 10:1327–1334PubMedCrossRefGoogle Scholar
  96. 96.
    Johnson JD, Ahmed NT, Luciani DS, Han Z, Tran H, Fujita J, et al (2003) Increased islet apoptosis in Pdx1+/− mice. J. Clin. Invest 111:1147–1160PubMedGoogle Scholar
  97. 97.
    Hui H, Perfetti R (2002) Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. Eur J Endocrinol 146:129–141PubMedCrossRefGoogle Scholar
  98. 98.
    Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15:106–110PubMedCrossRefGoogle Scholar
  99. 99.
    Stoffers DA, Ferrer J, Clarke WL, Habener JF (1997) Early onset type-II diabetes mellitus (MODY 4) linked to IPF1. Nat Genet 17:138–139PubMedCrossRefGoogle Scholar
  100. 100.
    Hani EH, Stoffers DA, Chevre JC, Durand E, Stanojevic V, Dina C, et al (1999) Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J Clin Invest 104:R41–R48PubMedCrossRefGoogle Scholar
  101. 101.
    Verfaillie CM (2005) Multipotent adult progenitor cells: an update. Novartis Found Symp 265:55–61; discussion 61–65, 92–97PubMedCrossRefGoogle Scholar
  102. 102.
    Verfaillie C (2005) Stem cell plasticity. Hematology 10:293–296PubMedCrossRefGoogle Scholar
  103. 103.
    Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, Atkinson MA, et al (2004) In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes 53:1721–1732PubMedCrossRefGoogle Scholar
  104. 104.
    Ianus A, Holz GG, Theise ND, Hussain MA (2003) In vivo derivation of glucosecompetent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111:843–850PubMedGoogle Scholar
  105. 105.
    Hess D, Li L, Martin M, Sakano S, Hill D, Strutt B, et al (2003) Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol 21:763–770PubMedCrossRefGoogle Scholar
  106. 106.
    Mathews V, Hanson PT, Ford E, Fujita J, Polonsky KS, Graubert TA (2004) Recruitment of bone marrow-derived endothelial cells to sites of pancreatic beta-cell injury. Diabetes 53:91–98PubMedCrossRefGoogle Scholar
  107. 107.
    Karnieli O, Izhar-Prato Y, Bulvik S, Efrat S (2007) Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation. Stem Cells 5:5Google Scholar
  108. 108.
    Yoshida S, Kajimoto Y, Yasuda T, Watada H, Fujitani Y, Kosaka H, et al (2002) PDX-1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells. Diabetes 51:2505–2513PubMedCrossRefGoogle Scholar
  109. 109.
    Kojima H, Nakamura T, Fujita Y, Kishi A, Fujimiya M, Yamada S, et al (2002) Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin. Diabetes 51:1398–1408PubMedCrossRefGoogle Scholar
  110. 110.
    Desmet VJ (2001) Organization principles. In: Arias IM, Boyer JL, Chisari FV, Fausto N, Schachter D, Shafritz DA (eds) The liver; biology and pathobiology, 4th edn. Lippincott Williams and Wilkins, Philadelphia, PA, pp 3–15Google Scholar
  111. 111.
    Thorgeirsson SS (1996) Hepatic stem cells in liver regeneration. FASEB J 10:1249–1256PubMedGoogle Scholar
  112. 112.
    Deutsch G, Jung J, Zheng M, Lora J, Zaret KS (2001) A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development 128:871–881PubMedGoogle Scholar
  113. 113.
    Otsuka M, Hoshida Y, Kato N, Moriyama M, Taniguchi H, Arai M, et al (2003) Liver chip and gene shaving. J Gastroenterol 38:89–92PubMedGoogle Scholar
  114. 114.
    Shen CN, Horb ME, Slack JM, Tosh D (2003) Transdifferentiation of pancreas to liver. Mech Dev 120:107–116PubMedCrossRefGoogle Scholar
  115. 115.
    Yang H, Morrison CM, Conlon JM, Laybolt K, Wright JR, Jr (1999) Immunocytochemical characterization of the pancreatic islet cells of the Nile Tilapia (Oreochromis niloticus). Gen Comp Endocrinol 114:47–56PubMedCrossRefGoogle Scholar
  116. 116.
    Kito H, Ose Y, Mizuhira V, Sato T, Ishikawa T, Tazawa T (1982) Separation and purification of (Cd, Cu, Zn)-metallothionein in carp hepato-pancreas. Comp Biochem Physiol C 73:121–127PubMedCrossRefGoogle Scholar
  117. 117.
    Sigal SH, Brill S, Fiorino AS, Reid LM (1992) The liver as a stem cell and lineage system. Am J Physiol 263:G139–G148PubMedGoogle Scholar
  118. 118.
    Yang L, Li S, Hatch H, Ahrens K, Cornelius JG, Petersen BE, et al (2002) In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormoneproducing cells. Proc Natl Acad Sci USA 99:8078–8083PubMedCrossRefGoogle Scholar
  119. 119.
    Zalzman M, Gupta S, Giri RK, Berkovich I, Sappal BS, Karnieli O, et al (2003) Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. Proc Natl Acad Sci USA 100:7253–7258PubMedCrossRefGoogle Scholar
  120. 120.
    Zalzman M, Anker-Kitai L, Efrat S (2005) Differentiation of human liver-derived, insulin-producing cells toward the {beta}-cell phenotype. Diabetes 54:2568–2575PubMedCrossRefGoogle Scholar
  121. 121.
    Sapir T, Shternhall K, Meivar-Levy I, Blumenfeld T, Cohen H, Skutelsky E, et al (2005) From the Cover: Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells. Proc Natl Acad Sci USA 102:7964–7969PubMedCrossRefGoogle Scholar
  122. 122.
    Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, et al (2003) NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 9:596–603PubMedCrossRefGoogle Scholar
  123. 123.
    Horb ME, Shen CN, Tosh D, Slack JM (2003) Experimental conversion of liver to pancreas. Curr Biol 13:105–115PubMedCrossRefGoogle Scholar
  124. 124.
    Ber I, Shternhall K, Perl S, Ohanuna Z, Goldberg I, Barshack I, et al (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. J Biol Chem 278: 31950–31957PubMedCrossRefGoogle Scholar
  125. 125.
    Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, et al (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 6:568–572PubMedCrossRefGoogle Scholar
  126. 126.
    Jungermann K (1987) Metabolic zonation of liver parenchyma: significance for the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. Diabetes Metab Rev 3:269–293PubMedGoogle Scholar
  127. 127.
    Hashimshony T, Zhang J, Keshet I, Bustin M, Cedar H (2003) The role of DNA methylation in setting up chromatin structure during development. Nat Genet 34:187–192PubMedCrossRefGoogle Scholar
  128. 128.
    Chakrabarti SK, Francis J, Ziesmann SM, Garmey JC, Mirmira RG (2003) Covalent histone modifications underlie the developmental regulation of insulin gene transcription in pancreatic beta cells. J Biol Chem 278:23617–23623PubMedCrossRefGoogle Scholar
  129. 129.
    Chakrabarti SK, Mirmira RG (2003) Transcription factors direct the development and function of pancreatic b-cells. Trends Endocrinol Metab 14:78–84PubMedCrossRefGoogle Scholar
  130. 130.
    Mosley AL, Ozcan S (2003) Glucose regulates insulin gene transcription by hyperacetylation of histone h4. J Biol Chem 278:19660–19666PubMedCrossRefGoogle Scholar
  131. 131.
    Hall DB, Struhl K (2002) The VP16 activation domain interacts with multiple transcriptional components as determined by protein-protein cross-linking in vivo. J Biol Chem 277:46043–46050PubMedCrossRefGoogle Scholar
  132. 132.
    Memedula S, Belmont AS (2003) Sequential recruitment of HAT and SWI/SNF components to condensed chromatin by VP16. Curr Biol 13:241–246PubMedCrossRefGoogle Scholar
  133. 133.
    Tumbar T, Sudlow G, Belmont AS (1999) Large-scale chromatin unfolding and remodeling induced by VP16 acidic activation domain. J Cell Biol 145:1341–1354PubMedCrossRefGoogle Scholar
  134. 134.
    Kaneto H, Nakatani Y, Miyatsuka T, Matsuoka TA, Matsuhisa M, Hori M, et al (2005) PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes 54:1009–1022PubMedCrossRefGoogle Scholar
  135. 135.
    Kaneto H, Matsuoka TA, Nakatani Y, Miyatsuka T, Matsuhisa M, Hori M, et al (2005) A crucial role of MafA as a novel therapeutic target for diabetes. J Biol Chem 280:15047–15052PubMedCrossRefGoogle Scholar
  136. 136.
    Imai J, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Uno K, et al (2005) Constitutively active PDX1 induced efficient insulin production in adult murine liver. Biochem Biophys Res Commun 326:402–409PubMedCrossRefGoogle Scholar
  137. 137.
    Meivar-Levy I, Sapir T, Gefen-Halevi S, Aviv V, Barshack I, Onaca N, et al (2007) PDX-1 induces hepatic dedifferentiation by suppressing expression of C/EBPb. Hepatology: Epub ahead of time Aug 17Google Scholar
  138. 138.
    Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, et al (1997) Diabetes, defective pancreatic morphogenisis, and abnormal enteronendocrine differentiation in BETA2/NeuroD-deficient mice. Genes Dev 11:2323–2334PubMedCrossRefGoogle Scholar
  139. 139.
    Demeterco C, Beattie GM, Dib SA, Lopez AD, Hayek A (2000) A role for activin A and betacellulin in human fetal pancreatic cell differentiation and growth. J Clin Endocrinol Metab 85:3892–3897PubMedCrossRefGoogle Scholar
  140. 140.
    Koizumi M, Doi R, Toyoda E, Tulachan SS, Kami K, Mori T, Ito D, Kawaguchi Y, Fujimoto K, Gittes GK, Imamura M (2004) Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver. Surgery 136:449–457PubMedCrossRefGoogle Scholar
  141. 141.
    Shternhall-Ron K, Quintana FJ, Perl S, Meivar-Levy I, Barshack I, Cohen IR, et al (2007) Ectopic PDX-1 expression in liver ameliorates type 1 diabetes. J Autoimmun 28:134–142PubMedCrossRefGoogle Scholar
  142. 142.
    Cao LZ, Tang DQ, Horb ME, Li SW and Yang LJ (2004) High glucose is necessary for complete maturation of Pdx1-VP16-expressing hepatic cells into functional insulinproducing cells. Diabetes 53:3168–3178PubMedCrossRefGoogle Scholar
  143. 143.
    Nakajima-Nagata N, Sakurai T, Mitaka T, Katakai T, Yamato E, Miyazaki J, Tabata Y, Sugai M and Shimizu A (2004) In vitro induction of adult hepatic progenitor cells into insulin-producing cells. Biochem Biophys Res Commun 318:625–630PubMedCrossRefGoogle Scholar
  144. 144.
    Li W, Horb MT, Tosh D, Slack JM (2005) In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech Dev 122:835–847PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Irit Meivar-Levy
    • 1
  • Sarah Ferber
    • 2
    • 1
  1. 1.Endocrine InstituteSheba Medical CenterTel-HashomerIsrael
  2. 2.Department of Human Genetics and Molecular Medicine, Sackler School of MedicineTel-Aviv UniversityTel-AvivIsrael

Personalised recommendations