Skip to main content

Advertisement

SpringerLink
Log in

Transdifferentiation of human adipose tissue-derived stromal cells into insulin-producing clusters

  • Original Article
  • Published:
Journal of Artificial Organs Aims and scope Submit manuscript

Abstract

Type 1 diabetes mellitus is caused by autoimmune destruction of insulin-producing beta cells. The major obstacle to transplantation of insulin-producing cells to cure the disease is the limited source of these cells. To overcome this problem, we describe here a multistep protocol for generation of insulin-producing islet-like clusters from human adipose tissue-derived stromal cells (ADSCs). Analysis using reverse transcription polymerase chain reaction detected enhanced expression of various pancreatic genes during the differentiation of ADSCs. Immunofluorescence analysis revealed functional similarities between cells derived from ADSCs and pancreatic islet cells, i.e., the presence of insulin- and C-peptide-coexpressing cells in the clusters and glucagon expression on the cell surface. The glucose challenge tests revealed the production of insulin, and such production was regulated via physiological signaling pathways. Our insulin-producing cells derived from ADSCs could be potentially used for cell therapy of type 1 diabetes mellitus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Epidemiology of diabetes interventions and complications research group. sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the epidemiology of diabetes interventions and complications (edic) study. jama 2003;290:2159–2167

    Article  Google Scholar 

  2. 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

    Article  PubMed  CAS  Google Scholar 

  3. Robertson RP. Islet transplantation as a treatment for diabetes — a work in progress. N Engl J Med 2004;350:6940–705

    Article  Google Scholar 

  4. Soria B, Roche E, Berna G, León-Ouinto T, Reig JA, Martin F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 2000;49:157–162

    Article  PubMed  CAS  Google Scholar 

  5. Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M. Insulin production by human embryonic stem cells. Diabetes 2001;50:1691–1697

    Article  PubMed  CAS  Google Scholar 

  6. 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 2001;292:1389–1393

    Article  PubMed  CAS  Google Scholar 

  7. Kahan BW, Jacobson LM, Hullett DA, Ochoada JM, Oberley TD, Lang KM, Odorico JS. Pancreatic precursors and differentiated islet cell types from murine embryonic stem cells: an in vitro model to study islet differentiation. Diabetes 2003;52:2016–2024

    Article  PubMed  CAS  Google Scholar 

  8. Leon-Quinto T, Jones J, Skoudy A, Burcin M, Soria B. In vitro directed differentiation of mouse embryonic stem cells into insulinproducing cells. Diabetologia 2004;47:1442–1451

    Article  PubMed  CAS  Google Scholar 

  9. 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

    Article  PubMed  CAS  Google Scholar 

  10. Djian P, Roncari DAK, Hollenberg CH. Influence of anatomic site and age on the replication and differentiation of rat adipocyte precursors in culture. J Clin Invest 1983;72:1200–1208

    Article  PubMed  CAS  Google Scholar 

  11. Komoda H, Miyagawa S, Omori T, Takahagi Y, Murakami H, Shigehisa T, Ito T, Matsuda H, Shirakura R. Survival of adult islet grafts from transgenic pigs with N-acetylglucosaminyltransferase-III (GnT-III) in cynomolgus monkeys. Xenotransplantation 2005;12:209–216

    Article  PubMed  Google Scholar 

  12. Seaberg RM, Smukler SR, Kieffer TJ, Enikolopov G, Asghar Z, Wheeler MB, Korbutt G, van der Kooy D. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol 2004;22:1115–1124

    Article  PubMed  CAS  Google Scholar 

  13. Zalzman M, Gupta S, Giri RK, Berkovich I, Sappal BS, Karnieli O, Zern MA, Fleischer N, Efrat S. Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. Proc Natl Acad Sci USA 2003;100:7253–7258

    Article  PubMed  CAS  Google Scholar 

  14. Yang L, Li S, Hatch H, Ahrens K, Comelius 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

    Article  PubMed  CAS  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. 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

    PubMed  CAS  Google Scholar 

  17. Ebert R, Ulmer M, Zeck S, Meissner-Weigl J, Schneide D, Stopper H, Schpp N, Kassem M, Jacob F. Selenium supplementation restores the antioxidative capacity and prevents cell damage in bone marrow stromal cells in vitro. Stem Cells 2006;24:1226–1235

    Article  PubMed  CAS  Google Scholar 

  18. Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Müller 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

    Article  PubMed  CAS  Google Scholar 

  19. 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

    Article  PubMed  CAS  Google Scholar 

  20. Eberhardt M, Salmon P, von Mach MA, Hengstler JG, Brulport M, Linscheid P, Seboek D, Oberholzer J, Barbero A, Martin I, Müller B, Trono D, Zulewski H. Multipotential nestin and Isl-1 positive mesenchymal stem cells isolated from human pancreatic islets. Biochem Biophys Res Commun 2006;345:1167–1176

    Article  PubMed  CAS  Google Scholar 

  21. Kang SK, Putnam LA, Ylostalo J, Popescu IR, Dufour J, Belousov A, Bunnell BA. Neurogenesis of Rhesus adipose stromal cells. J Cell Sci 2004;17:289–299

    Google Scholar 

  22. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003;52:1–8

    Article  PubMed  CAS  Google Scholar 

  23. Schuldiner M, Yanuka O, Itskovitz-Eldor J, Melton DA, Benvenisty N. From the cover: effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci USA 2000;97:11307–11312

    Article  PubMed  CAS  Google Scholar 

  24. Soria B. In vitro differentiation of pancreatic beta-cells. Differentiation 2001;68:205–219

    Article  PubMed  CAS  Google Scholar 

  25. Ogneva V, Martinova Y. The effect of in vitro fibroblast growth factors on cell proliferation in pancreas from normal and streptozotocin-treated rats. Diabetes Res Clin Pract 2002;57:11–16

    Article  PubMed  CAS  Google Scholar 

  26. Otonkoski T, Beattie GM, Mally MI, Ricordi C, Hayek A. Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells. J Clin Invest 1993;92:1459–1466

    Article  PubMed  CAS  Google Scholar 

  27. Vaca P, Berna G, Martin F, Soria B. Nicotinamide induces both proliferation and differentiation of embryonic stem cells into insulin-producing cells. Transplant Proc 2003;5:2021–2023

    Article  Google Scholar 

  28. Xu G, Stoffers DA, Habner JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999;48:2270–2276

    Article  PubMed  CAS  Google Scholar 

  29. Abraham EJ, Leech CA, Lin JC, Zulewski H, Habener JF. Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulinproducing cells. Endocrinology 2002;143:3152–3161

    Article  PubMed  CAS  Google Scholar 

  30. Itkin-Ansari P, Demeterco C, Bossie S, de la Tour DD, Beattie GM, Movassat J, Mally MI, Hayek A, Levine F. PDX-1 and cell-cell contact act in synergy to promote delta-cell development in a human pancreatic endocrine precursor cell line. Mol Endocrinol 2000;14:814–822

    Article  PubMed  CAS  Google Scholar 

  31. 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

    Article  PubMed  CAS  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. Sun Y, Chen L, Hou XG, Hou WK, Dong JJ, Sun L, Tang KX, Wang B, Song J, Li H, Wang KX. Differentiation of bone marrowderived mesenchymal stem cells from diabetic patients into insulinproducing cells in vitro. Clin Med J 2007;120:771–776

    CAS  Google Scholar 

  34. Timper K, Seboek D, Eberhardt M, Linscheid P, Christ-Crain M, Keller U, Müller B, Zulewski H. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin-, somatostatin-, and glucagon-expressing cells. Biochem Biophys Res Commun 2006;341:1135–1140

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Hanayuki Okura, Yuichi Fumimoto, Toshirou Nishida & Yoshiki Sawa

  2. Japan Society for the Promotion of Science, Tokyo, Japan

    Hanayuki Okura

  3. Laboratory for Somatic Stem Cell Therapy, Foundation of Biomedical Research and Innovation, TRI305, 1-5-4 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan

    Hiroshi Komoda & Akifumi Matsuyama

  4. Medical Center for Translational Research, Osaka University Hospital, Osaka, Japan

    Chun-Man Lee & Akifumi Matsuyama

Authors
  1. Hanayuki Okura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Komoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuichi Fumimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-Man Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshirou Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoshiki Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akifumi Matsuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akifumi Matsuyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okura, H., Komoda, H., Fumimoto, Y. et al. Transdifferentiation of human adipose tissue-derived stromal cells into insulin-producing clusters. J Artif Organs 12, 123–130 (2009). https://doi.org/10.1007/s10047-009-0455-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10047-009-0455-6

Key words

Search

Navigation