Skip to main content

Advertisement

SpringerLink
Log in

Effect and mechanisms of human Wharton’s jelly-derived mesenchymal stem cells on type 1 diabetes in NOD model

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Type 1 diabetes is an autoimmune disease that results from an inflammatory destruction of β-cells in islets. Mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) own a peculiar immunomodulatory feature and might reverse the inflammatory destruction and repair the function of β-cells. Sixty NOD mice were divided into four groups, including normal control group, WJ-MSCs prevention group (before onset), WJ-MSCs treatment group (after onset), and diabetic control group. After homologous therapy, onset time of diabetes, levels of fasting plasma glucose (FPG), fed blood glucose and C-peptide, regulation of cytokines, and islet cells were examined and evaluated. After WJ-MSCs infusion, FPG and fed blood glucose in WJ-MSCs treatment group decreased to normal level in 6-8 days and maintained for 6 weeks. Level of fasting C-peptide of these mice was higher compared to diabetic control mice (P = 0.027). In WJ-MSCs prevention group, WJ-MSCs played a protective role for 8-week delayed onset of diabetes, and fasting C-peptide in this group was higher compared to the other two diabetic groups (P = 0.013, 0.035). Compared with diabetic control group, frequencies of CD4+CD25+Foxp3+ Tregs in WJ-MSCs prevention group and treatment group were higher, while levels of IL-2, IFN-γ, and TNF-α were lower (P < 0.001); the degree of insulitis was also depressed, especially for WJ-MSCs prevention group(P < 0.05). Infusion of WJ-MSCs could aid in T1DM through regulation of the autoimmunity and recovery of islet β-cells no matter before or after onset of T1DM. WJ-MSCs might be an effective method for T1DM.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. M. Kornete, E.S. Mason, C.A. Piccirillo, Immune regulation in T1D and T2D: prospective role of Foxp3+ treg cells in disease pathogenesis and treatment. Front. Endocrinol. (Lausanne) 4, 76 (2013)

    Google Scholar 

  2. H. Ishigame, L.A. Zenewicz, S. Sanjabi, P. Licona-Limón, M. Nakayama, W.J. Leonard, R.A. Flavell, Excessive Th1 responses due to the absence of TGF-β signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. Proc. Natl. Acad. Sci. USA 110, 6961–6966 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. R. Montandon, S. Korniotis, E. Layseca-Espinosa, C. Gras, J. Mégret, S. Ezine, M. Dy, F. Zavala, Innate pro-B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells. Proc. Natl. Acad. Sci. USA 110, E2199–E2208 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. A. Zaldumbide, G. Alkemade, F. Carlotti, T. Nikolic, J.R. Abreu, M.A. Engelse, A. Skowera, E.J. de Koning, M. Peakman, B.O. Roep, R.C. Hoeben, E.J. Wiertz, Genetically engineered human islets protected from CD8-mediated autoimmune destruction in vivo. Mol. Ther. 21, 1592–1601 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. D.M. Gravano, K.K. Hoyer, Promotion and prevention of autoimmune disease by CD8+ T cells. J. Autoimmun. 45, 68–79 (2013)

    Article  CAS  PubMed  Google Scholar 

  6. F. Haseda, A. Imagawa, Y. Murase-Mishiba, J. Terasaki, T. Hanafusa, CD4(+) CD45RA(−) FoxP3(high) activated regulatory T cells are functionally impaired and related to residual insulin-secreting capacity in patients with type 1 diabetes. Clin. Exp. Immunol. 173, 207–216 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. C. Zhang, L. Gui, Y. Xu, T. Wu, D. Liu, Preventive effects of andrographolide on the development of diabetes in autoimmune diabetic NOD mice by inducing immune tolerance. Int. Immunopharmacol. 16, 451–456 (2013)

    Article  CAS  PubMed  Google Scholar 

  8. V. Machado Cde, P.D. Telles, I.L. Nascimento, Immunological characteristics of mesenchymal stem cells. Rev. Bras. Hematol. Hemoter 35, 62–67 (2013)

    Article  PubMed  Google Scholar 

  9. M. Mohyeddin Bonab, M. Mohajeri, M.A. Sahraian, M. Yazdanifar, A. Aghsaie, A. Farazmand, B. Nikbin, Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells. Arch. Med. Res. 44, 266–272 (2013)

    Article  CAS  PubMed  Google Scholar 

  10. E.W. Choi, I.S. Shin, S.Y. Park, J.H. Park, J.S. Kim, E.J. Yoon, S.K. Kang, J.C. Ra, S.H. Hong, Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation. Arthritis Rheum. 64, 243–253 (2012)

    Article  CAS  PubMed  Google Scholar 

  11. R. Ciccocioppo, M.E. Bernardo, A. Sgarella, R. Maccario, M.A. Avanzini, C. Ubezio, A. Minelli, C. Alvisi, A. Vanoli, F. Calliada, P. Dionigi, C. Perotti, F. Locatelli, G.R. Corazza, Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut 60, 788–798 (2011)

    Article  PubMed  Google Scholar 

  12. D.J. Kota, L.L. Wiggins, N. Yoon, R.H. Lee, TSG-6 produced by hMSCs delays the onset of autoimmune diabetes by suppressing Th1 development and enhancing tolerogenicity. Diabetes 62, 2048–2058 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. A.E. Aksu, E. Horibe, J. Sacks, R. Ikeguchi, J. Breitinger, M. Scozio, J. Unadkat, M. Feili-Hariri, Co-infusion of donor bone marrow with host mesenchymal stem cells treats GVHD and promotes vascularized skin allograft survival in rats. Clin. Immunol. 127, 348–358 (2008)

    Article  CAS  PubMed  Google Scholar 

  14. M.P. De Miguel, S. Fuentes-Julián, A. Blázquez-Martínez, C.Y. Pascual, M.A. Aller, J. Arias, F. Arnalich-Montiel, Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr. Mol. Med. 12, 574–591 (2012)

    Article  PubMed  Google Scholar 

  15. R. Atoui, R.C. Chiu, Immune responses after mesenchymal stem cell implantation. Methods Mol. Biol. 1036, 107–120 (2013)

    Article  PubMed  Google Scholar 

  16. L. Caja, E. Bertran, J. Campbell, N. Fausto, I. Fabregat, The transforming growth factor-beta (TGF-β) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells. J. Cell. Physiol. 226, 1214–1223 (2011)

    Article  CAS  PubMed  Google Scholar 

  17. M.M. Duffy, J. Pindjakova, S.A. Hanley, C. McCarthy, G.A. Weidhofer, E.M. Sweeney, K. English, G. Shaw, J.M. Murphy, F.P. Barry, B.P. Mahon, O. Belton, R. Ceredig, M.D. Griffin, Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell–cell contact and mediated by prostaglandin E2 via the EP4 receptor. Eur. J. Immunol. 41, 2840–2851 (2011)

    Article  CAS  PubMed  Google Scholar 

  18. D.W. Kim, M. Staples, K. Shinozuka, P. Pantcheva, S.D. Kang, C.V. Borlongan, Wharton’s jelly-derived mesenchymal stem cells: phenotypic characterization and optimizing their therapeutic potential for clinical applications. Int. J. Mol. Sci. 14, 11692–11712 (2013)

    Article  PubMed Central  PubMed  Google Scholar 

  19. J. Hu, X. Yu, Z. Wang, F. Wang, L. Wang, H. Gao, Y. Chen, W. Zhao, Z. Jia, S. Yan, Y. Wang, Long term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus. Endocr. J. 60, 347–357 (2013)

    Article  CAS  PubMed  Google Scholar 

  20. N.E. Davis, D. Hamilton, M.J. Fontaine, Harnessing the immunomodulatory and tissue repair properties of mesenchymal stem cells to restore β cell function. Curr. Diab. Rep. 12, 612–622 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Y. Ding, D. Xu, G. Feng, A. Bushell, R.J. Muschel, K.J. Wood, Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58, 1797–1806 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. C.L. Rackham, P.C. Chagastelles, N.B. Nardi, A.C. Hauge-Evans, P.M. Jones, A.J. King, Co- transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. Diabetologia 54, 1127–1135 (2011)

    Article  CAS  PubMed  Google Scholar 

  23. J.L. Reading, J.H. Yang, S. Sabbah, A. Skowera, R.R. Knight, J. Pinxteren, B. Vaes, T. Allsopp, A.E. Ting, S. Busch, A. Raber, R. Deans, T.I. Tree, Clinical-grade multipotent adult progenitor cells durably control pathogenic T cell responses in human models of transplantation and autoimmunity. J. Immunol. 190, 4542–4552 (2013)

    CAS  PubMed  Google Scholar 

  24. J. Stagg, J. Galipeau, Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. Curr. Mol. Med. 13, 856–867 (2013)

    Article  CAS  PubMed  Google Scholar 

  25. C. Xu, P. Yu, X. Han, L. Du, J. Gan, Y. Wang, Y. Shi, TGF-β promotes immune responses in the presence of mesenchymal stem cells. J. Immunol. 192, 103–109 (2014)

    Article  CAS  PubMed  Google Scholar 

  26. A.U. Engela, C.C. Baan, N.H. Litjens, M. Franquesa, M.G. Betjes, W. Weimar, M.J. Hoogduijn, Mesenchymal stem cells control alloreactive CD8(+) CD28(−) T cells. Clin. Exp. Immunol. 174, 449–458 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. R. Zhang, Y. Liu, K. Yan, L. Chen, X.R. Chen, P. Li, F.F. Chen, X.D. Jiang, Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J. Neuroinflammation 10, 106 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. L. Quintana-Lopez, M. Blandino-Rosano, G. Perez-Arana, A. Cebada-Aleu, A. Lechuga-Sancho, M. Aguilar-Diosdado, C. Segundo, Nitric oxide is a mediator of antiproliferative effects induced by proinflammatory cytokines on pancreatic beta cells. Mediators Inflamm. 2013, 905175 (2013)

    Article  PubMed Central  PubMed  Google Scholar 

  29. B.M. Tan, N.W. Zammit, A.O. Yam, R. Slattery, S.N. Walters, E. Malle, S.T. Grey, Baculoviral inhibitors of apoptosis repeat containing (BIRC) proteins fine-tune TNF-induced nuclear factor κB and c-Jun N-terminal kinase signalling in mouse pancreatic beta cells. Diabetologia 56, 520–532 (2013)

    Article  CAS  PubMed  Google Scholar 

  30. S. Talebi, A. Aleyasin, M. Soleimani, M. Massumi, Derivation of islet-like cells from mesenchymal stem cells using PDX1-transducing lentiviruses. Biotechnol. Appl. Biochem. 59, 205–212 (2012)

    Article  CAS  PubMed  Google Scholar 

  31. P.J. Tsai, H.S. Wang, Y.M. Shyr, Z.C. Weng, L.C. Tai, J.F. Shyu, T.H. Chen, Transplantation of insulin-producing cells from umbilical cord mesenchymal stem cells for the treatment of streptozotocin-induced diabetic rats. J. Biomed. Sci. 19, 47 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. S.J. Kim, Y.S. Choi, E.S. Ko, S.M. Lim, C.W. Lee, D.I. Kim, Glucose-stimulated insulin secretion of various mesenchymal stem cells after insulin-producing cell differentiation. J. Biosci. Bioeng. 113, 771–777 (2012)

    Article  CAS  PubMed  Google Scholar 

  33. P. Lin, L. Chen, D. Li, N. Yang, Y. Sun, Y. Xu, Dynamic analysis of bone marrow mesenchymal stem cells migrating to pancreatic islets using coculture microfluidic chips: an accelerated migrating rate and better survival of pancreatic islets were revealed. Neuro. Endocrinol. Lett. 30, 204–208 (2009)

    PubMed  Google Scholar 

  34. G.I. Bell, H.C. Broughton, K.D. Levac, D.A. Allan, A. Xenocostas, D.A. Hess, Transplanted human bone marrow progenitor subtypes stimulate endogenous islet regeneration and revascularization. Stem. Cells. Dev. 21, 97–109 (2012)

    Article  CAS  PubMed  Google Scholar 

  35. H. Yagi, A. Soto-Gutierrez, B. Parekkadan, Y. Kitagawa, R.G. Tompkins, N. Kobayashi, M.L. Yarmush, Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant. 19, 667–679 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  36. R.H. Lee, M.J. Seo, R.L. Reger, J.L. Spees, A.A. Pulin, S.D. Olson, D.J. Prockop, Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc. Natl. Acad. Sci. USA 103, 17438–17443 (2006)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. F. Ezquer, M. Ezquer, D. Contador, M. Ricca, V. Simon, P. Conget, The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells 30, 1664–1674 (2012)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We appreciate all work done by Wenlong Yu and Jiangsu Yu in this study.

Ethical standards

The experiments comply with the current laws of the country in which they were performed. This study was approved by the Institutional Animal Ethical Committee, Qingdao and Ethics Committee of the Affiliated Hospital of Medical College, Qingdao University.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Stem Cell Research Center, The Affiliated Hospital of Medical College, Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, China

    Jianxia Hu, Yangang Wang, Li Wang & Hong Gao

  2. Endocrinology Department, The Affiliated Hospital of Medical College, Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, China

    Fang Wang, Luan Wang, Xiaolong Yu, Ruixia Sun, Zhongchao Wang, Zhengju Fu, Wenjuan Zhao & Shengli Yan

Authors
  1. Jianxia Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yangang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaolong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ruixia Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhongchao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hong Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhengju Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wenjuan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shengli Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shengli Yan.

Additional information

Jianxia Hu and Yangang Wang have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hu, J., Wang, Y., Wang, F. et al. Effect and mechanisms of human Wharton’s jelly-derived mesenchymal stem cells on type 1 diabetes in NOD model. Endocrine 48, 124–134 (2015). https://doi.org/10.1007/s12020-014-0219-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-014-0219-9

Keywords

Search

Navigation