Abstract
The transplantation of insulin-producing cells is a promising option for the treatment of patients suffering from diabetes. Because the amount of transplantable surrogate islets is limited, pluripotent stem cells characterized by self-renewal and differentiation capacity offer unique alternatives for regenerative medicine. Over the last years, embryonic stem (ES) cells isolated from early embryos of mouse and human origin have been used for in vitro differentiation into the endoderm and pancreatic lineages. The application of various differentiation strategies resulted in the formation of insulin-producing cells, but only partially, ES-derived insulin-secreting clusters were able to normalize the blood glucose level of diabetic mice. Recently, induced pluripotent stem (iPS) cells have been established by reprogramming of adult cells via the transfer of pluripotency-associated genes. These iPS cells were also capable to differentiate into insulin-positive cells. Here, we present a short overview about the strategies established for the generation of insulin-producing cells from murine and human pluripotent ES and iPS cells. The data demonstrate the achievements that have been obtained with respect to the production of islet-like cells, but also underline that future efforts are needed to improve their functional status and to translate laboratory data into clinical application.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Amabile G and Meissner A (2009) Induced pluripotent stem cells: current progress and potential for regenerative medicine. Trends Mol Med 15:59–68
Assady S, Maor G et al (2001) Insulin production by human embryonic stem cells. Diabetes 50:1691–1697
Blyszczuk P, Asbrand C et al (2004) Embryonic stem cells differentiate into insulin-producing cells without selection of nestin-expressing cells. Int J Dev Biol 48:1095–1104
Blyszczuk P, Czyz J et al (2003) Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci USA 100:998–1003
Bonner-Weir S and Weir GC (2005) New sources of pancreatic beta-cells. Nat Biotechnol 23:857–861
Bonner-Weir S and Weir GC (2009) Insulin-producing cells derived from stem cells: a potential treatment for diabetes. In: Lanza R (ed) Essentials of stem cell biology, 2nd edn. Elsevier, Amsterdam, pp. 731–737
Boretti MI and Gooch KJ (2007) Transgene expression level and inherent differences in target gene activation determine the rate and fate of neurogenin3-mediated islet cell differentiation in vitro. Tissue Eng 13:775–788
Borowiak M, Maehr R et al (2009) Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem Cell 4:348–358
Boyd AS, Wu DC et al (2008) A comparison of protocols used to generate insulin-producing cell clusters from mouse embryonic stem cells. Stem Cells 26:1128–1137
Chen S, Borowiak M et al (2009) A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol 5:258–265
D’Amour KA, Bang AG et al (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392–1401
Guo T and Hebrok M (2009) Stem cells to pancreatic beta-cells: new sources for diabetes cell therapy. Endocr Rev 30:214–227
Gurdon JB and Melton DA (2008) Nuclear reprogramming in cells. Science 322:1811–1815
Hansson M, Tonning A et al (2004) Artifactual insulin release from differentiated embryonic stem cells. Diabetes 53:2603–2609
He L and Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522–531
Hori Y, Rulifson IC et al (2002) Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci USA 99:16105–16110
Huangfu D, Maehr R et al (2008) Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26:795–797
Izumikawa M, Minoda R et al (2005) Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11:271–276
Jiang J, Au M et al (2007) Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25:1940–1953
Jiang W, Bai Z et al (2008) Differentiation of mouse nuclear transfer embryonic stem cells into functional pancreatic beta cells. Diabetologia 51:1671–1679
Johansson KA, Dursun U et al (2007) Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell 12:457–465
Kahan BW, Jacobson LM et al (2003) Pancreatic precursors and differentiated islet cell types from murine embryonic stem cells: an in vitro model to study islet differentiation. Diabetes 52:2016–2024
Kaji K, Norrby K et al (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458:771–775
Kim D, Kim CH et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472–476
Kroon E, Martinson LA et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26:443–452
Landgraf P, Rusu M et al (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414
Lanza RP, Dresser BL et al (2000) Cloning Noah’s ark. Sci Am 283:84–89
Lavon N, Yanuka O et al (2006) The effect of overexpression of Pdx1 and Foxa2 on the differentiation of human embryonic stem cells into pancreatic cells. Stem Cells 24:1923–1930
Leon-Quinto T, Jones J et al (2004) In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia 47:1442–1451
Liew CG, Shah NN et al (2008) PAX4 enhances beta-cell differentiation of human embryonic stem cells. PLoS One 3:e1783
Lumelsky N, Blondel O et al (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394
Marchand M, Schroeder IS et al (2009) Mouse ES cells over-expressing the transcription factor NeuroD1 show increased differentiation towards endocrine lineages and insulin-expressing cells. Int J Dev Biol 53:569–578
Marenah L, McCluskey JT et al (2006) 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 387:941–947
McLean AB, D’Amour KA et al (2007) Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. Stem Cells 25:29–38
Miyazaki S, Yamato E et al (2004) Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes 53:1030–1037
Moritoh Y, Yamato E et al (2003) Analysis of insulin-producing cells during in vitro differentiation from feeder-free embryonic stem cells. Diabetes 52:1163–1168
Nakanishi M, Hamazaki TS et al (2007) Pancreatic tissue formation from murine embryonic stem cells in vitro. Differentiation 75:1–11
Phillips BW, Hentze H et al (2007) Directed differentiation of human embryonic stem cells into the pancreatic endocrine lineage. Stem Cells Dev 16:561–578
Poy MN, Eliasson L et al (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432:226–230
Ptasznik A, Beattie GM et al (1997) Phosphatidylinositol 3-kinase is a negative regulator of cellular differentiation. J Cell Biol 137:1127–1136
Rajagopal J, Anderson WJ et al (2003) Insulin staining of ES cell progeny from insulin uptake. Science 299:363
Rolletschek A and Wobus AM (2009) Induced human pluripotent stem cells: promises and open questions. Biol Chem 390:845–849
Schwitzgebel VM, Scheel DW et al (2000) Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127:3533–3542
Segev H, Fishman B et al (2004) Differentiation of human embryonic stem cells into insulin-producing clusters. Stem Cells 22:265–274
Shapiro AM, Lakey JR et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238
Shapiro AM, Ricordi C et al (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330
Shi Y, Desponts C et al (2008) Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3:568–574
Shi Y, Hou L et al (2005) Inducing embryonic stem cells to differentiate into pancreatic beta cells by a novel three-step approach with activin A and all-trans retinoic acid. Stem Cells 23:656–662
Shim JH, Kim SE et al (2007) Directed differentiation of human embryonic stem cells towards a pancreatic cell fate. Diabetologia 50:1228–1238
Soldner F, Hockemeyer D et al (2009) Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136:964–977
Soria B, Roche E et al (2000) Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157–162
Stefani G and Slack FJ (2008) Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol 9:219–230
Sulzbacher S, Schroeder IS et al (2009) Activin A-induced differentiation of embryonic stem cells into endoderm and pancreatic progenitors-the influence of differentiation factors and culture conditions. Stem Cell Rev Rep 5:159–173
Takahashi K, Tanabe K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872
Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
Takeuchi JK and Bruneau BG (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459:708–711
Tateishi K, He J et al (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 283:31601–31607
Thomson JA, Itskovitz-Eldor J et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147
Treff NR, Vincent RK et al (2006) Differentiation of embryonic stem cells conditionally expressing neurogenin 3. Stem Cells 24:2529–2537
Vaca P, Berna G et al (2003) Nicotinamide induces both proliferation and differentiation of embryonic stem cells into insulin-producing cells. Transplant Proc 35:2021–2023
Vaca P, Martin F et al (2006) Induction of differentiation of embryonic stem cells into insulin-secreting cells by fetal soluble factors. Stem Cells 24:258–265
Vincent R, Treff N et al (2006) Generation and characterization of novel tetracycline-inducible pancreatic transcription factor-expressing murine embryonic stem cell lines. Stem Cells Dev 15:953–962
Waddington CH (1957) The strategies of genes. Allan & Unwin, London
Wagers AJ and Weissman IL (2004) Plasticity of adult stem cells. Cell 116:639–648
Wajchenberg BL (2007) beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev 28:187–218
Weintraub H, Tapscott SJ et al (1989) Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc Natl Acad Sci USA 86:5434–5438
Wobus AM and Boheler KR (2005) Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol Rev 85:635–678
Woltjen K, Michael IP et al (2009) piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458:766–770
Xie H, Ye M et al (2004) Stepwise reprogramming of B cells into macrophages. Cell 117:663–676
Xu X, Kahan B et al (2006) Endoderm and pancreatic islet lineage differentiation from human embryonic stem cells. Cloning Stem Cells 8:96–107
Yu J, Hu K et al (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324:797–801
Yu J, Vodyanik MA et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920
Zhang D, Jiang W et al (2009) Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res 19:429–438
Zhou Q, Brown J et al (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455:627–632
Zhou Q and Melton DA (2008) Extreme makeover: converting one cell into another. Cell Stem Cell 3:382–388
Zhou H, Wu S et al (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4:381–384
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media B.V.
About this paper
Cite this paper
Schroeder, I.S., Daniel-Wojcik, A., Wobus, A.M. (2012). Strategies for Pancreatic Differentiation of Pluripotent Stem Cells. In: Jenkins, N., Barron, N., Alves, P. (eds) Proceedings of the 21st Annual Meeting of the European Society for Animal Cell Technology (ESACT), Dublin, Ireland, June 7-10, 2009. ESACT Proceedings, vol 5. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0884-6_28
Download citation
DOI: https://doi.org/10.1007/978-94-007-0884-6_28
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-0883-9
Online ISBN: 978-94-007-0884-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)