Horm Metab Res 2008; 40(2): 155-161
DOI: 10.1055/s-2007-1022553
Review

© Georg Thieme Verlag KG Stuttgart · New York

Generation of Insulin-producing Beta Cells from Stem Cells - Perspectives for Cell Therapy in Type 1 Diabetes

J. Seissler 1 , M. Schott 2
  • 1Medical Clinic Innenstadt, Ludwig-Maximilians-University, Munich, Germany
  • 2Department of Endocrinology, Heinrich Heine University, Duesseldorf, Germany
Further Information

Publication History

received 09.10.2007

accepted 26.10.2007

Publication Date:
19 February 2008 (online)

Abstract

Cell based therapy for the treatment of type 1 diabetes is limited by the overall shortage of donor organs for transplantation. This is the rationale for the research on the generation of insulin-producing beta cells from an inexhaustible source of cells such as the stem cells. Stem cells are progenitor cells which possess the capacity of self-renewing and differentiation in fully mature cells depending on the culture conditions. The fundamental question is how to make terminally matured pancreatic beta cells. During the last years different approaches for the neogenesis of beta cells have been described using embryonic stem cells, adult stem cells residing in the pancreas, or other nonpancreatic cell types. Although fully functional islets have not yet been derived from any stem cells, the use of stem cells is still the most promising approach on the way to establish a treatment protocol for the cure of type 1 diabetes in the future.

References

  • 1 Shapiro AM, Lakey JR, 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
  • 2 Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM. Five-year follow-up after clinical islet transplantation.  Diabetes. 2005;  54 2060-2069
  • 3 Murtaugh LC, Melton DA. Genes, signals, and lineages in pancreas development.  Annu Rev Cell Dev Biol. 2003;  19 71-89
  • 4 Jensen J. Gene regulatory factors in pancreatic development.  Dev Dynamics. 2004;  229 176-200
  • 5 Habener JF, Kemp DM, Thomas MK. Minireview: transcriptional regulation in pancreatic development.  Endocrinology. 2005;  146 1025-1034
  • 6 Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice.  Nature. 1994;  371 606-609
  • 7 Hui H, Perfetti R. Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood.  Eur J Endocrinol. 2002;  146 129-141
  • 8 Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage: NGN3+cells are islet progenitors and are distinct from duct progenitors.  Development. 2002;  129 2447-2457
  • 9 Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice.  Genes Dev. 1997;  11 2323-2334
  • 10 Ahlgren U, Pfaff SL, Jessell TM, Edlund T, Edlund H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells.  Nature. 1997;  385 257-260
  • 11 Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, Schwitzgebel V, Hayes-Jordan A, German M. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of β-cell formation in the pancreas.  Development. 2000;  127 5533-5540
  • 12 Dohrmann C, Gruss P, Lemaire L. Pax genes and the differentiation of hormone-producing endocrine cells in the pancreas.  Mech Dev. 2000;  92 47-54
  • 13 Cissell MA, Zhao L, Sussel L, Henderson E, Stein R. Transcription factor occupancy of the insulin gene in vivo Evidence for direct regulation by Nkx2.2.  J Biol Chem. 2003;  278 751-756
  • 14 Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner-Weir S, Sharma A. A switch from MafB to MafA expression accompanies differentiation to pancreatic β-cells.  Dev Biol. 2006;  293 526-539
  • 15 Sussel L, Kalamaras J, Hartigan-O’Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells.  Development. 1998;  125 2213-2221
  • 16 Matsuoka TA, Kaneto H, Stein R, Miyatsuka T, Kawamori D, Henderson E, Kojima I, Matsuhisa M, Hori M, Yamasaki Y. MafA regulates expression of genes important to islet {beta} cell function.  Mol Endocrinol. 2007;  21 2764-2774
  • 17 Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, MyKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets.  Science. 2001;  292 1389-1394
  • 18 Blyszczuk P, Asbrand C, Rozzo A, Kania G, St-Onge L, Rupnik M, Wobus AM. Embryonic stem cells differentiate into insulin-producing cells without selection of nestin expressing cells.  Int J Dev Biol. 2004;  48 1095-1104
  • 19 Segev H, Fishman B, Ziskind A, Shulman M, Itskovitz-Eldor J. Differentiation of human embryonic stem cells into insulin-producing clusters.  Stem Cells. 2004;  22 265-274
  • 20 Marenah L, MacCluskey JT, Abdel-Wahab YH, O’Harte FP, MacClenaghan NH, Flatt PR. A stable analogue of glucose-dependent insulinotropic polypeptide, GIP(LysPAL16), enhances functional differentiation of mouse embryonic stem cells into cells expressing islet-specific genes and hormones.  Biol Chem. 2006;  387 941-947
  • 21 Brolen GK, Heiuns H, Edsbagge J, Semb H. Signals from the embryonic mouse pancreas induce differentiation of human embryonic stem cells into insulin-producing beta-cell-like cells.  Diabetes. 2005;  54 2867-2874
  • 22 Rajagopal J, Anderson WJ, Kume S, Martinez OI, Melton DA. Insulin staining of ES cell progeny from insulin uptake.  Science. 2003;  299 363
  • 23 Hansson M, Tonning A, Frandsen U, Pedri A, Rajagopal J, Englund MC, Heller RS, Hakannson J, Fleckner J, Skold HN, Melton DA, Semb H, Serup P. Insulin release form differentiated embryonic stem cells.  Diabetes. 53;  2004 2603-2609
  • 24 D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE. Efficient differentiation of human embryonic stem cells to definitive endoderm.  Nat Biotechnol. 2005;  23 1534-1541
  • 25 Baharvand H, Jafary H, Massumi M, Ashtiani SK. Generation of insulin-secreting cells from human embryonic stem cells.  Dev Growth Differ. 2006;  48 323-332
  • 26 Jiang J, Au M, Lu K, Eshpeter A, Korbutt G, Fisk G, Majumdar AS. Generation of insulin-producing islet-like clusters from human embryonic stem cells.  Stem Cells. 2007;  25 1940-1953
  • 27 Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L, Wobus AM. Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells.  Proc Natl Acad Sci USA. 2003;  100 998-1003
  • 28 Leon-Quinto T, Jones J, Skoudy A, Burcin M, Soria B. In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells.  Diabetologia. 2004;  47 1442-1451
  • 29 Fujikawa T, Oh SH, Pi L, Hatch HM, Shupe T, Petersen BE. Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells.  Am J Pathol. 2005;  166 1781-1791
  • 30 Madsen OD. Stem cells and diabetes treatment.  APMIS. 2005;  113 858-875
  • 31 Bouwens L, Rooman I. Regulation of pancreatic beta-cell mass.  Physiol Rev. 2005;  85 1255-1270
  • 32 Flier SN, Kulkarni RN, Kahn CR. Evidence for a circulating islet cell growth factor in insulin-resistant states.  Proc Natl Acad Sci USA. 2001;  98 7475-7480
  • 33 Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels.  Science. 2001;  294 564-567
  • 34 Lipsett M, Finegood DT. Beta-cell neogenesis during prolonged hyperglycemia in rats.  Diabetes. 2002;  51 1834-1841
  • 35 Paris M, Bernard-Kargar C, Berthault MF, Bouwens L, Ktorza A. Specific and combined effects of insulin and glucose on functional pancreatic beta-cell mass in vivo in adult rats.  Endocrinology. 2003;  144 2717-2727
  • 36 Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.  Nature. 2004;  429 41-46
  • 37 Georgia S, Bhushan A. Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass.  J Clin Invest. 2004;  114 963-968
  • 38 Gershengorn MC, Hardikar AA, Wei C, Geras-Raaka E, Marcus-Samuels M, Raaka MB. Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells.  Science. 2004;  306 2261-2264
  • 39 Lechner A, Nolan AL, Blacken RA, Habener JF. Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue.  Biochem Biophys Res Commun. 2005;  327 581-588
  • 40 Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development.  Diabetes. 1993;  42 1715-1720
  • 41 Wang RN, Kloppel G, Bouwens L. Duct - to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats.  Diabetologia. 1995;  38 1405-1411
  • 42 Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O’Neil JJ. In vitro cultivation of human islets from expanded ductal tissue.  Proc Natl Acad Sci USA. 2000;  97 7999-8004
  • 43 Gao R, Ustinov J, Pulkkinen MA, Lundin K, Korsgren O, Otonkoski T. Characterization of endocrine progenitor cells and critical factors for their differentiation in human adult pancreatic cell culture.  Diabetes. 2003;  52 2007-2015
  • 44 Ogata T, Park KY, Seno M, Kojima I. Reversal of streptozotocin- induced hyperglycemia by transplantation of pseudoislets consisting of β-cells derived from ductal cells.  Endocr J. 2004;  51 381-386
  • 45 Hao E, Tyrberg B, Itkin-Ansari P, Lakey JR. Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas.  Nat Med. 2006;  12 310-316
  • 46 Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells.  Nat Med. 2000;  6 278-282
  • 47 Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK, Habener JF. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes.  Diabetes. 2001;  50 521-533
  • 48 Guz Y, Nasir I, Teitelman G. Regeneration of pancreatic beta cells from intra-islet precursor cells in an experimental model of diabetes.  Endocrinology. 2001;  142 4956-1468
  • 49 Selander L, Edlund H. Nestin is expressed in mesenchymal and not epithelial cells of the developing mouse pancreas.  Mech Dev. 2002;  113 189-192
  • 50 Delacour A, Nepote V, Trumpp A, Herrera PL. Nestin expression in pancreatic exocrine cell lineages.  Mech Dev. 2004;  121 3-14
  • 51 Bernardo AS, Barrow J, Hay CW. et al . Presence of endocrine and exocrine markers in EGFP-positive cells from the developing pancreas of a nestin/EGFP mouse.  Mol Cell Endocrinol. 2006;  253 14-21
  • 52 Seaberg RM, Smukler SR, Kieffer TJ, Enikolopov, Asghar Z, Wheeler MB, Korbutt G, Kooy D van der. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages.  Nat Biotechnol. 2004;  22 1115-1124
  • 53 Suzuki A, Nakauchi H, Taniguchi H. Prospective isolation of multipotent pancreatic progenitors using flowcytometric cell sorting.  Diabetes. 2004;  53 2143-2152
  • 54 Deutsch G, Jung J, Zheng M, Lora J, Zaret KS. A bipotential precursor population for pancreas and liver within the embryonic endoderm.  Development. 2001;  128 871-881
  • 55 Shen CN, Slack JM, Tosh D. Molecular basis of transdifferentiation of pancreas to liver.  Nat Cell Biol. 2000;  2 879-887
  • 56 Grompe M. Pancreatic-hepatic switches in vivo.  Mech Dev. 2003;  120 99-106
  • 57 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
  • 58 Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, Chan L. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice.  Nat Med. 2003;  9 596-603
  • 59 Yang L, Li S, Hatch H, Ahrens K, Cornelius JG, Petersen BE, Peck AB. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells.  Proc Natl Acad Sci USA. 2002;  99 8078-8083
  • 60 Imai J, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Uno K, Hasegawa Y, Gao J, Ishihara H, Sasano H, Mizuguchi H, Asano T, Oka Y. Constitutively active PDX1 induced efficient insulin production in adult murine liver.  Biochem Biophys Res Commun. 2005;  326 402-409
  • 61 Li WC, Horb ME, Tosh D, Slack JM. In vitro transdifferentiation of hepatoma cells into functional pancreatic cells.  Mech Dev. 2005;  122 835-847
  • 62 Sapir T, Shternhall K, Meivar-Levy I, Blumenfeld T, Cohen H, Skutelsky E, Eventov-Friedman S, Barshack I, Goldberg I, Pri-Chen S, Ben-Dor L, Polak-Charcon S, Karasik A, Shimon I, Mor E, Ferber S. Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells.  Proc Natl Acad Sci USA. 2005;  102 7964-7969
  • 63 Zalzmann M, Anker-Kitai L, Efrat S. Differentiation of human liver-derived, insulin-producing cells toward the beta-cell phenotype.  Diabetes. 2005;  54 2568-2575
  • 64 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
  • 65 Yoshida S, Kajimoto Y, Yasuda T, Watada H, Fujitani Y, Kosaka H, Gotow T, Miyatsuka T, Umayahara Y, Yamasaki Y, Hori M. PDX-1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells.  Diabetes. 2002;  51 2505-2513
  • 66 Ianus A, Holz GG, Theise ND, Hussain MA. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion.  J Clin Invest. 2003;  111 843-850
  • 67 Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice.  Science. 2003;  302 1223-1237
  • 68 Nishio J, Gaglia JL, Turvey SE, Campbell C, Benoist C, Mathis D. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution.  Science. 2006;  311 1775-1778
  • 69 Suri A, Calderon B, Esparza TJ, Frederick K, Bittner P, Unanue ER. Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells.  Science. 2006;  311 1778-1780
  • 70 Chong AS, Shen J, Tao J, Yin D, Kuznetsov A, Hara M, Philipson LH. Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration.  Science. 2006;  311 1774-1775
  • 71 Lechner A, Yang YG, Blacken RA, Wang L, Nolan AL, Habener JF. No evidence for significant transdifferentiation of bone marrow into pancreatic beta-cells in vivo.  Diabetes. 2004;  53 616-623
  • 72 Hess D, Li L, Martin M, Sakano S, Hill D, Strutt B, Thyssen S, Gray DA, Bhatia M. Bone marrow-derived stem cells initiate pancreatic regeneration.  Nat Biotechnol. 2003;  21 763-770
  • 73 Ruhnke M, Ungefroren H, Nussler A. et al . Differentiation of in vitro-modified human peripheral blood monocytes into hepatocyte-like and pancreatic islet-like cells.  Gastroenterology. 2005;  128 1774-1786
  • 74 Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells.  Proc Natl Acad Sci USA. 2003;  100 2426-2431
  • 75 Oh SH, Muzzonigro TM, Bae SH, LaPlante JM, Hatch HM, Petersen BE. Adult bone marrow-derived cells trans-differentiating into insulin-producing cells for the treatment of type I diabetes.  Lab Invest. 2004;  84 607-617
  • 76 Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, Atkinson MA, Yang LJ. In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow.  Diabetes. 2004;  53 1721-1732
  • 77 Moriscot C, Fraipont F de, Richard MJ. et al . Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro.  Stem Cells. 2005;  23 594-603
  • 78 Karnieli O, Izhar-Prato Y, Bulvik S, Efrat S. Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation.  Stem Cells. 2007;  25 2837-2844
  • 79 Timper K, Seboek D, Eberhardt M. et al . Human adipose tissue- derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells.  Biochem Biophys Res Commun. 2006;  341 1135-1140
  • 80 Wu XH, Liu CP, Xu KF, Mao XD, Zhu J, Jiang JJ, Cui D, Zhang M, Xu Y, Liu C. Reversal of hyperglycemia in diabetic rats by portal vein transplantation of islet-like cells generated from bone marrow mesenchymal stem cells.  World J Gastroenterol. 2007;  13 3342-3349

Correspondence

J. SeisslerMD 

Diabetes Center

Medical Clinic Innenstadt

Ludwig-Maximilians-University Munich

Ziemssenstraße 1

80336 Munich

Germany

Phone: +49/89/5160 21 86

Fax: +49/89/5160 49 56

Email: jochen.seissler@med.uni-muenchen.de

    >