Growth and development of the islets of Langerhans: Implications for the treatment of diabetes mellitus

Current Opinion in Pharmacology

Volumn 1, Issue 6, 2001, Pages 641-649

  Docherty, Kevin ^a  

^a UNIVERSITY OF ABERDEEN   (United Kingdom)

Author keywords

B cell lines; Development; Endocrinology; Islet cell ontogeny; Islet transplantation; Pharmacology; Stem cells; Techniques Methods; Transcription factors

Indexed keywords

TRANSCRIPTION FACTOR;

ANIMAL; CELL DIFFERENTIATION; CELL LINEAGE; CELL TRANSPLANTATION; CYTOLOGY; EMBRYOLOGY; GROWTH, DEVELOPMENT AND AGING; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; NON INSULIN DEPENDENT DIABETES MELLITUS; PANCREAS; PANCREAS ISLET; PANCREAS ISLET TRANSPLANTATION; PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION; STEM CELL;

ANIMAL; CELL DIFFERENTIATION; CELL LINEAGE; CELL TRANSPLANTATION; DIABETES MELLITUS, INSULIN-DEPENDENT; DIABETES MELLITUS, NON-INSULIN-DEPENDENT; HUMAN; ISLETS OF LANGERHANS; ISLETS OF LANGERHANS TRANSPLANTATION; PANCREAS; SIGNAL TRANSDUCTION; STEM CELLS; TRANSCRIPTION FACTORS;

EID: 0035650959     PISSN: 14714892     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1471-4892(01)00109-6     Document Type: Review

References (62)

1. 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. 329:1993;977-986.
2. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet. 352:1998;837-853.
3. Shapiro A.M., Lakey J.R., Ryan E.A., Korbutt G.S., Toth E., Warnock G.L., Kneteman N.M., Rajotte R.V. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. New Engl J Med. 343:2000;230-238. This paper describes a protocol for the successful transplantation of islets. This provided impetus towards finding a replenishable source of glucose-sensitive insulin-secreting cells to meet the demand for donor tissue.
4. + cells derived from human islets. Diabetes. 48:1999;1013-1019.
5. Halvorsen T.L., Leibowitz G., Levine F. Telomerase activity is sufficient to allow transformed cells to escape from crisis. Mol Cell Biol. 19:1999;1864-1870.
6. Edlund H. Developmental biology of the pancreas. Diabetes. 50:2001;S5-S9.
7. McKinnon C.M., Docherty K. Pancreatic duodenal homeobox-1, PDX-1, a major regulator of β cell function and identity. Diabetologia. 44:2001;1203-1214.
8. Jonsson J., Carlsson L., Edlund T., Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 371:1994;606-609.
9. Offield M.F., Jetton T.L., Labosky P.A., Ray M., Stein R.W., Magnuson M.A., Hogan B.L., Wright C.V. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development. 122:1996;983-995.
10. Ben-Shushan E., Marshak S., Shoshkes M., Cerasi E., Melloul D. A pancreatic β-cell-specific enhancer in the human Pdx-1 gene is regulated by HNF-3β, HNF-1α and SPs transcription factors. J Biol Chem. 276:2001;17533-17540.
11. Sund N.J., Vatamaniuk M.Z., Casey M., Ang S.L., Magnuson M.A., Stoffers D.A., Matschinsky F.M., Kaestner K.H. Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia. Genes Dev. 15:2001;1706-1715.
12. Li H., Arber S., Jessell T.M., Edlund H. Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9. Nat Genet. 23:1999;67-70.
13. Harrison K.A., Thaler J., Pfaff S.L., Gu H., Kehrl J.H. Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet. 23:1999;71-75.
14. Pfaff S.L., Mendelsohn M., Stewart C.L., Edlund T., Jessell T.M. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell. 84:1996;309-320.
15. Ahlgren U., Pfaff S.L., Jessell T.M., Edlund T., Edlund H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature. 385:1997;257-260.
16. Krapp A., Knofler M., Ledermann B., Burki K., Berney C., Zoerkler N., Hagenbuchle O., Wellauer P.K. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 12:1998;3752-3763.
17. Apelqvist A., Li H., Sommer L., Beatus P., Anderson D.J., Honjo T., Hrabe D., Angelis M., Lendahl U., Edlund H. Notch signalling controls pancreatic cell differentiation. Nature. 400:1999;877-881.
18. Gradwohl G., Dierich A., LeMeur M., Guillemot F. neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA. 97:2000;1607-1611. The authors showed that ngn3-positive cells coexpress neither insulin nor glucagon, suggesting that ngn3 marks early precursors of pancreatic endocrine cells. The ngn3 knockout mouse failed to generate any pancreatic endocrine cells.
19. Schwitzgebel V.M., Scheel D.W., Conners J.R., Kalamaras J., Lee J.E., Anderson D.J., Sussel L., Johnson J.D., German M.S. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development. 127:2000;3533-3542. This paper reports that overexpression of ngn3 under the control of the PDX-1 promoter was sufficient to drive differentiation of islet cells. The islet cells produced, however, were overwhelmingly α cells. This suggests that other factors are required to drive ngn3-positive cells from an α cell default pathway.
20. Sussel L., Kalamaras J., Hartigan-O'Connor D.J., Meneses J.J., Pedersen R.A., Rubenstein J.L., German M.S. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development. 125:1998;2213-2221.
21. Sander M., Sussel L., Conners J., Scheel D., Kalamaras J., Dela C.F., Schwitzgebel V., Hayes-Jordan A., German M. Homeobox gene nkx6.1 lies downstream of nkx2.2 in the major pathway of Beta-cell formation in the pancreas. Development. 127:2000;5533-5540. This study established a requirement for Nkx6.1 downstream of Nkx2.2 in β-cell development. Nkx6.1 mediates the expansion and final differentiation of β-cell progenitors.
22. Sosa-Pineda B., Chowdhury K., Torres M., Oliver G., Gruss P. The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature. 386:1997;399-402.
23. St-Onge L., Sosa-Pineda B., Chowdhury K., Mansouri A., Gruss P. Pax6 is required for differentiation of glucagon-producing α-cells in mouse pancreas. Nature. 387:1997;406-409.
24. Sander M., Neubuser A., Kalamaras J., Ee H.C., Martin G.R., German M.S. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev. 11:1997;1662-1673.
25. Naya F.J., Huang H.P., Qiu Y., Mutoh H., DeMayo F.J., Leiter A.B., Tsai M.J. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 11:1997;2323-2334.
26. Kim S.K., Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev. 15:2001;111-127.
27. Hebrok M., Kim S.K., Melton D.A. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 12:1998;1705-1713.
28. -/- mutant mice had a threefold increase in pancreas mass and a fourfold increase in pancreatic endocrine cell numbers.
29. Thomas M.K., Rastalsky N., Lee J.H., Habener J.F. Hedgehog signaling regulation of insulin production by pancreatic β-cells. Diabetes. 49:2000;2039-2047.
30. Thomas M.K., Lee J.H., Rastalsky N., Habener J.F. Hedgehog signaling regulation of homeodomain protein islet duodenum homeobox-1 expression in pancreatic β-cells. Endocrinology. 142:2001;1033-1040.
31. Miralles F., Czernichow P., Scharfmann R. Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development. 125:1998;1017-1024.
32. Jensen J., Pedersen E.E., Galante P., Hald J., Heller R.S., Ishibashi M., Kageyama R., Guillemot F., Serup P., Madsen O.D. Control of endodermal endocrine development by Hes-1. Nat Genet. 24:2000;36-44. Mice deficient in Hes-1 exhibited accelerated differentiation of endocrine cells. This study provided evidence that Hes-1 is a negative regulator of endodermal endocrine differentiation and emphasised the key role of Delta/Notch signalling, ngn3 and Hes-1 in regulating islet progenitor-cell activity.
33. 5 integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells. J Cell Biol. 150:2000;1445-1460.
34. Miralles F., Battelino T., Czernichow P., Scharfmann R. TGF-β plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2. J Cell Biol. 143:1998;827-836.
35. Miettinen P.J., Huotari M., Koivisto T., Ustinov J., Palgi J., Rasilainen S., Lehtonen E., Keski-Oja J., Otonkoski T. Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors. Development. 127:2000;2617-2627.
36. Dahl U., Sjodin A., Semb H. Cadherins regulate aggregation of pancreatic β-cells in vivo. Development. 122:1996;2895-2902.
37. Guz Y., Montminy M.R., Stein R., Leonard J., Gamer L.W., Wright C.V., Teitelman G. Expression of murine STF-1, a putative insulin gene transcription factor, in β cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Development. 121:1995;11-18.
38. Jensen J., Heller R.S., Funder-Nielsen T., Pedersen E.E., Lindsell C., Weinmaster G., Madsen O.D., Serup P. Independent development of pancreatic α- and β-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes. 49:2000;163-176. This immunohistochemical study of various markers (mainly transcription factors and hormones) during development of the mouse pancreas found a temporal sequence of gene activation and inactivation that differed between α and β cells. Results indicated that α and β cells arose separately from a ngn3-positive progenitor cell.
39. Herrera P.L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development. 127:2000;2317-2322. Mice in which cells that transcribed the insulin, glucagon, PP, and PDX-1 genes were tagged with Cre-recombinase and mated with mice in which the insulin and glucagon promoters drove expression of hGH, which was downstream of a loxP-flanked transcription termination site. The glucagon promoter was inactive in the insulin-promoter tagged cells and vice versa, suggesting that α and β cells differentiate from independent cell lineages.
40. Finegood D.T., Scaglia L., Bonner-Weir S. Dynamics of β-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes. 44:1995;249-256.
41. Bonner-Weir S. Islet growth and development in the adult. J Mol Endocrinol. 24:2000;297-302.
42. Sharma A., Zangen D.H., Reitz P., Taneja M., Lissauer M.E., Miller C.P., Weir G.C., Habener J.F., Bonner-Weir S. The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes. 48:1999;507-513.
43. Xu G., Stoffers D.A., Habener J.F., Bonner-Weir S. Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 48:1999;2270-2276.
44. Heimberg H., Bouwens L., Heremans Y., Van De Casteele M., Lefebvre V., Pipeleers D. Adult human pancreatic duct and islet cells exhibit similarities in expression and differences in phosphorylation and complex formation of the homeodomain protein Ipf-1. Diabetes. 49:2000;571-579.
45. Stoffers D.A., Kieffer T.J., Hussain M.A., Drucker D.J., Bonner-Weir S., Habener J.F., Egan J.M. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes. 49:2000;741-748.
46. Hui H., Wright C., Perfetti R. Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells. Diabetes. 50:2001;785-796.
47. Ramiya V.K., Maraist M., Arfors K.E., Schatz D.A., Peck A.B., Cornelius J.G. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med. 6:2000;278-282. This article describes the growth of pancreatic ductal epithelial cells from NOD mice. With time in culture, these cells showed changes in the pattern of expression of differentiation markers.
48. Bonner-Weir S., Taneja M., Weir G.C., Tatarkiewicz K., Song K.H., Sharma A., O'Neil J.J. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA. 97:2000;7999-8004. These authors showed that human duct-cell preparations could be expanded in culture and directed to differentiate into glucose-responsive islet tissue.
49. Zulewski H., Abraham E.J., Gerlach M.J., Daniel P.B., Moritz W., Muller B., Vallejo M., Thomas M.K., Habener J.F. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes. 50:2001;521-533. This paper describes the presence of nestin-positive cells within rat and human islet preparations. These represent mutipotential islet-progenitor cells that exhibit an extended proliferative capacity in culture.
50. Macfarlane W.M., Cragg H., Docherty H.M., Read M.L., James R.F., Aynsley-Green A., Docherty K. Impaired expression of transcription factor IUF1 in a pancreatic β-cell line derived from a patient with persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis). FEBS Lett. 413:1997;304-308.
51. Macfarlane W.M., Chapman J.C., Shepherd R.M., Hashmi M.N., Kamimura N., Cosgrove K.E., O'Brien R.E., Barnes P.D., Hart A.W., Docherty H.M., et al. Engineering a glucose-responsive human insulin-secreting cell line from islets of Langerhans isolated from a patient with persistent hyperinsulinemic hypoglycemia of infancy. J Biol Chem. 274:1999;34059-34066.
52. Soria B., Skoudy A., Martin F. From stem cells to beta cells: new strategies in cell therapy of diabetes mellitus. Diabetologia. 44:2001;407-415.
53. Soria B., Roche E., Berna G., Leon-Quinto T., Reig J.A., Martin F. Insulin secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes. 49:2000;157-162. This study used a cell-trapping approach to clone and expand an insulin-secreting cell line from mouse embryonic stem cells.
54. Lumelsky N., Blondel O., Laeng P., Velasco I., Ravin R., McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science. 292:2001;1389-1394. This paper describes culture conditions that allowed expansion of nestin-positive cells from mouse embryonic cells, such that these cells could then be induced to express insulin and other β-cell phenotypic markers.
55. Assady S., Maor G., Amit M., Itskovitz-Eldor J., Skorecki K.L., Tzukerman M. Insulin production by human embryonic stem cells. Diabetes. 50:2001;1691-1697. Showed that under certain culture conditions human embryonic stem cells spontaneously differentiated to produce insulin-secreting cells. Properties of these cells were partially characterised within a heterogeneous population.
56. Thomson J.A., Itskovitz-Eldor J., Shapiro S.S., Waknitz M.A., Swiergiel J.J., Marshall V.S., Jones J.M. Embryonic stem cell lines derived from human blastocysts. Science. 282:1998;1145-1147.
57. Gussoni E., Soneoka Y., Strickland C.D., Buzney E.A., Khan M.K., Flint A.F., Kunkel L.M., Mulligan R.C. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 401:1999;390-394.
58. Jackson K.A., Mi T., Goodell M.A. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA. 96:1999;14482-14486.
59. Shen C.N., Slack J.M., Tosh D. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol. 2:2000;879-887. The authors showed that a pancreatic cell line (AR42J-B13) and cultures of mouse embryonic pancreas could transdifferentiate into liver when treated with dexamethasone. This phenotypic conversion was associated with induction of the transcription factor c/EBPβ.
60. Ferber S., Halkin A., Cohen H., Ber I., Einav Y., Goldberg I., Barshack I., Seijffers R., Kopolovic J., Kaiser N., et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med. 6:2000;568-572. In vivo expression of PDX-1 in liver switched on the endogenous insulin genes in mice. This suggested the presence of adult stem cells and progenitor cells within the liver that could transdifferentiate to pancreatic endocrine cells upon exogenous expression of PDX-1.
61. Shaw J.A.M., Docherty K. Gene therapy for NIDDM - will it have a role? Hitman G.A. Towards Prediction and Prevention of NIDDM. 1999;369-381 John Wiley and Sons, Chichester.
62. Skipper M., Lewis J. Getting to the guts of enteroendocrine differentiation. Nat Genet. 24:2000;3-4.