Skip to main content
Log in

Differentiation of mesenchymal stem cells to insulin-producing cells and their impact on type 1 diabetic rats

  • Original Paper
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Cell therapy is thought to be a possible approach for treatment of diabetes. Cells with the ability to differentiate into insulin-producing cells (IPCs) would provide an unlimited source of islet cells for transplantation. In this study, the differentiation capacity of rat bone-marrow-derived mesenchymal stem cells (MSCs) to IPCs and the feasibility of using them for reversal of hyperglycemia were investigated. In vitro studies indicated that treatment of cells with high glucose concentration, nicotinamide and β-mercaptoethanol resulted to differentiated cells, which had characteristics of IPCs including spherical, grape-like morphology, secretion of insulin, and being positive for dithizone. To test the in vivo function of differentiated MSCs, they were injected into the spleen of diabetic rats. It was shown that diabetic rats who received IPCs, significantly reduced the glucose level, in response to intraperitoneal glucose tolerance (IPGT) test. These results indicate that MSCs are capable of in vitro differentiation into functional IPCs, which can reverse hyperglycemia in rat model of diabetes.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Atkinson MA, Eisenbarth GS (2001) Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 358:221–229

    Article  CAS  PubMed  Google Scholar 

  2. Roche E, Jones J, Arribas MI, Leon-Quinto T, Soria B (2006) Role of small bioorganic molecules in stem cell differentiation to insulin-producing cells. Bioorg Med Chem 14:6466–6474

    Article  CAS  PubMed  Google Scholar 

  3. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV (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  CAS  PubMed  Google Scholar 

  4. Mishra PK, Singh SR, Joshua IG, Tyagi SC (2010) Stem cells as a therapeutic target for diabetes. Front Biosci 15:461–477

    Article  PubMed  CAS  Google Scholar 

  5. Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F (2000) Insulin secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157–162

    Article  CAS  PubMed  Google Scholar 

  6. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Naujok O, Francini F, Jorns A, Lenzen S (2008) An efficient experimental strategy for mouse embryonic stem cell differentiation and separation of a cytokeratin-19-positive population of insulin-producing cells. Cell Prolif 41:607–624

    Article  CAS  PubMed  Google Scholar 

  9. Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O’Neill JJ (2000) In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 97:7999–8004

    Article  CAS  PubMed  Google Scholar 

  10. Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG (2000) Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med 6:278–282

    Article  CAS  PubMed  Google Scholar 

  11. Yang L, Li S, Hatch H, Ahrens K, Cornelius JG, Petersen BE, Peck AB (2002) In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormon producing cells. Proc Natl Acad Sci USA 99:8078–8083

    Article  CAS  PubMed  Google Scholar 

  12. Suzuki A, Nakauchi H, Taniguchi H (2003) Glucagon-like peptide 1 (1-37) converts intestinal epithelial cells into insulin-producing cells. Proc Natl Acad Sci USA 100:5034–5039

    Article  CAS  PubMed  Google Scholar 

  13. Choi KS, Shin JS, Lee JJ, Kim YS, Kim SB, Kim CW (2005) In vitro trans-differentiation of rat mesenchymal cells into insulin-producing cells by rat pancreatic extract. Biochem Biophys Res Commun 330:1299–1305

    Article  CAS  PubMed  Google Scholar 

  14. Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie CM (2001) Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98:2615–2625

    Article  CAS  PubMed  Google Scholar 

  15. Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, Atkinson MA, Yang LJ (2004) In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes 53:1721–1732

    Article  CAS  PubMed  Google Scholar 

  16. Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U (2004) Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci 45:4251–4255

    Article  PubMed  Google Scholar 

  17. Nakajima-Nagata N, Sakurai T, Mitaka T, Katakai T, Yamato E, Miyazaki J, Tabata Y, Sugai M, Shimizu A (2004) In vitro induction of adult hepatic progenitor cells into insulin-producing cells. Biochem Biophys Res Commun 318:625–630

    Article  CAS  PubMed  Google Scholar 

  18. Matsumoto R, Omura T, Yoshiyama M, Hayashi T, Inamoto S, Koh KR, Ohta K, Izumi Y, Nakamura Y, Akioka K, Kitaura Y, Takeuchi K, Yoshikawa J (2005) Vascular endothelial growth factor–expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction. Arterioscler Thromb Vasc Biol 25:1168–1173

    Article  CAS  PubMed  Google Scholar 

  19. Pereira RF, Halford KW, O’Hara MD, Leeper DB, Sokolov BP, Pollard MD, Bagasra O, Prockop DJ (1995) Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci USA 92:4857–4861

    Article  CAS  PubMed  Google Scholar 

  20. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    Article  CAS  PubMed  Google Scholar 

  21. Limbert C, Seufert J (2009) In vitro (re) programming of human bone marrow stromal cells toward insulin-producing phenotypes. Pediatr Diabetes 10:413–419

    Article  PubMed  Google Scholar 

  22. Ianus A, Holz GG, Theise ND, Hussain MA (2003) In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111:843–850

    CAS  PubMed  Google Scholar 

  23. Oh SH, Muzzonigro TM, Bae SH, LaPlante JM, Hatch HM, Petersen BE (2004) Adult bone marrow-derived cells transdifferentiating into insulin-producing cells for the treatment of type I diabetes. Lab Invest 84:607–617

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Soria B (2001) In vitro differentiation of pancreatic beta-cells. Differentiation 68:205–219

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Kojima H, Fujimiya M, Matsumura K, Nakahara T, Hara M, Chan L (2004) Extrapancreatic insulin-producing cells in multiple organs in diabetes. Proc Natl Acad Sci USA 101:2458–2463

    Article  CAS  PubMed  Google Scholar 

  28. Sun Y, Chen L, Hou XG, Hou WK, Dong JJ, Sun L, Tang KX, Wang B, Song J, Li H, Wang KX (2007) Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin-producing cells in vitro. Chin Med J 120:771–776

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK, Habener JF (2001) Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50:521–533

    Article  CAS  PubMed  Google Scholar 

  31. Chen LB, Jiang XB, Yang L (2004) Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells. World J Gastroenterol 10:3016–3020

    CAS  PubMed  Google Scholar 

  32. Shiroi A, Yoshikawa M, Yokota H, Fukui H, Ishizaka S, Tatsumi K, Takahashi Y (2002) Identification of insulin-producing cells drived from embryonic stem cells by zinc-chelating dithizone. Stem Cells 20:284–292

    Article  CAS  PubMed  Google Scholar 

  33. Latif ZA, Noel J, Alejandro R (1988) A simple method of staining fresh and cultured islets. Transplantation 45:827–830

    Article  CAS  PubMed  Google Scholar 

  34. Chausmer AB (1998) Zinc, insulin and diabetes. J Am Coll Nutr 17:109–115

    CAS  PubMed  Google Scholar 

  35. Rajagopal J, Anderson WJ, Kume S, Martinez OI, Melton DA (2003) Insulin staining of ES cells progeny from insulin uptake. Science 299:363

    PubMed  Google Scholar 

  36. Vaca P, Martin F, Vegara-Meseguer JM, Rovira JM, Berna G, Soria B (2006) Induction of differentiation of embryonic stem cells into insulin-secreting cells by fetal soluble factors. Stem Cells 24:258–265

    Article  CAS  PubMed  Google Scholar 

  37. Suys BE, Katier N, Rooman RP, Matthys D, Op De Beeck L, Du Caju MV, De Wolf D (2004) Female children and adolescents with type 1 diabetes have more pronounced early echocardiographic signs of diabetic cardiomyopathy. Diabetes Care 27:1947–1953

    Article  PubMed  Google Scholar 

  38. Saravanan R, Pari L (2005) Antihyperlipidemic and antiperoxidative effect of Diasulin, a polyherbal formulation in alloxan induced hyperglycemic rats. BMC Complement Altern Med 5:14

    Article  PubMed  Google Scholar 

  39. Patel SP, Katyare SS (2006) Effect of alloxan-diabetes and subsequent treatment with insulin on lipid/phospholipid composition of rat brain microsomes and mitochondria. Neurosci Lett 399:129–134

    Article  CAS  PubMed  Google Scholar 

  40. Macedo CS, Capelletti SM, Mercadante MCS, Padovan CR, Spadella CT (2002) Role of metabolic control on diabetic nephropathy. Acta Cir Bras 17:370–377

    Article  Google Scholar 

  41. Barreto EO, Riederer I, Arantes AC, Carvalho VF, Farias-Filho FA, Cordeiro RS, Martins MA, Savino W, e Silva PM (2005) Thymus involution in alloxan diabetes: analysis of mast cells. Mem Inst Oswaldo Cruz 100:127–130

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partly supported by a grant from the research office of Ferdowsi University of Mashhad, Iran. We would like to thank Dr. Jalal, Mr. Edalatmanesh and Mr. Bagheri for their great technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maryam M. Matin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neshati, Z., Matin, M.M., Bahrami, A.R. et al. Differentiation of mesenchymal stem cells to insulin-producing cells and their impact on type 1 diabetic rats. J Physiol Biochem 66, 181–187 (2010). https://doi.org/10.1007/s13105-010-0013-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-010-0013-y

Keywords

Navigation