Skip to main content

Strategies for Pancreatic Differentiation of Pluripotent Stem Cells

  • Conference paper
  • First Online:
  • 842 Accesses

Part of the book series: ESACT Proceedings ((ESACT,volume 5))

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Amabile G and Meissner A (2009) Induced pluripotent stem cells: current progress and potential for regenerative medicine. Trends Mol Med 15:59–68

    Article  PubMed  CAS  Google Scholar 

  • Assady S, Maor G et al (2001) Insulin production by human embryonic stem cells. Diabetes 50:1691–1697

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bonner-Weir S and Weir GC (2005) New sources of pancreatic beta-cells. Nat Biotechnol 23:857–861

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Guo T and Hebrok M (2009) Stem cells to pancreatic beta-cells: new sources for diabetes cell therapy. Endocr Rev 30:214–227

    Article  PubMed  CAS  Google Scholar 

  • Gurdon JB and Melton DA (2008) Nuclear reprogramming in cells. Science 322:1811–1815

    Article  PubMed  CAS  Google Scholar 

  • Hansson M, Tonning A et al (2004) Artifactual insulin release from differentiated embryonic stem cells. Diabetes 53:2603–2609

    Article  PubMed  CAS  Google Scholar 

  • He L and Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522–531

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Jiang J, Au M et al (2007) Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25:1940–1953

    Article  PubMed  CAS  Google Scholar 

  • Jiang W, Bai Z et al (2008) Differentiation of mouse nuclear transfer embryonic stem cells into functional pancreatic beta cells. Diabetologia 51:1671–1679

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kaji K, Norrby K et al (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458:771–775

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Landgraf P, Rusu M et al (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414

    Article  PubMed  CAS  Google Scholar 

  • Lanza RP, Dresser BL et al (2000) Cloning Noah’s ark. Sci Am 283:84–89

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Liew CG, Shah NN et al (2008) PAX4 enhances beta-cell differentiation of human embryonic stem cells. PLoS One 3:e1783

    Article  PubMed  Google Scholar 

  • Lumelsky N, Blondel O et al (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Nakanishi M, Hamazaki TS et al (2007) Pancreatic tissue formation from murine embryonic stem cells in vitro. Differentiation 75:1–11

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Poy MN, Eliasson L et al (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432:226–230

    Article  PubMed  CAS  Google Scholar 

  • Ptasznik A, Beattie GM et al (1997) Phosphatidylinositol 3-kinase is a negative regulator of cellular differentiation. J Cell Biol 137:1127–1136

    Article  PubMed  CAS  Google Scholar 

  • Rajagopal J, Anderson WJ et al (2003) Insulin staining of ES cell progeny from insulin uptake. Science 299:363

    PubMed  Google Scholar 

  • Rolletschek A and Wobus AM (2009) Induced human pluripotent stem cells: promises and open questions. Biol Chem 390:845–849

    Article  PubMed  CAS  Google Scholar 

  • Schwitzgebel VM, Scheel DW et al (2000) Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127:3533–3542

    PubMed  CAS  Google Scholar 

  • Segev H, Fishman B et al (2004) Differentiation of human embryonic stem cells into insulin-producing clusters. Stem Cells 22:265–274

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Shapiro AM, Ricordi C et al (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Shim JH, Kim SE et al (2007) Directed differentiation of human embryonic stem cells towards a pancreatic cell fate. Diabetologia 50:1228–1238

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Stefani G and Slack FJ (2008) Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol 9:219–230

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Takahashi K, Tanabe K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi JK and Bruneau BG (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459:708–711

    Article  PubMed  CAS  Google Scholar 

  • Tateishi K, He J et al (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 283:31601–31607

    Article  PubMed  CAS  Google Scholar 

  • Thomson JA, Itskovitz-Eldor J et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

    Article  PubMed  CAS  Google Scholar 

  • Treff NR, Vincent RK et al (2006) Differentiation of embryonic stem cells conditionally expressing neurogenin 3. Stem Cells 24:2529–2537

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Waddington CH (1957) The strategies of genes. Allan & Unwin, London

    Google Scholar 

  • Wagers AJ and Weissman IL (2004) Plasticity of adult stem cells. Cell 116:639–648

    Article  PubMed  CAS  Google Scholar 

  • Wajchenberg BL (2007) beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev 28:187–218

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Wobus AM and Boheler KR (2005) Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol Rev 85:635–678

    Article  PubMed  CAS  Google Scholar 

  • Woltjen K, Michael IP et al (2009) piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458:766–770

    Article  PubMed  CAS  Google Scholar 

  • Xie H, Ye M et al (2004) Stepwise reprogramming of B cells into macrophages. Cell 117:663–676

    Article  PubMed  CAS  Google Scholar 

  • Xu X, Kahan B et al (2006) Endoderm and pancreatic islet lineage differentiation from human embryonic stem cells. Cloning Stem Cells 8:96–107

    Article  PubMed  CAS  Google Scholar 

  • Yu J, Hu K et al (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324:797–801

    Article  PubMed  CAS  Google Scholar 

  • Yu J, Vodyanik MA et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zhou Q, Brown J et al (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455:627–632

    Article  PubMed  CAS  Google Scholar 

  • Zhou Q and Melton DA (2008) Extreme makeover: converting one cell into another. Cell Stem Cell 3:382–388

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Wu S et al (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4:381–384

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anna M. Wobus .

Editor information

Editors and Affiliations

Rights and permissions

Reprints 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

Publish with us

Policies and ethics