Advertisement

Intravenous Infusion of Human Adipose Tissue-Derived Mesenchymal Stem Cells to Treat Type 1 Diabetic Mellitus in Mice: An Evaluation of Grafted Cell Doses

  • Loan Thi-Tung Dang
  • Anh Nguyen-Tu Bui
  • Cong Le-Thanh Nguyen
  • Nhat Chau Truong
  • Anh Thi-Van Bui
  • Ngoc Phan Kim
  • Kiet Dinh Truong
  • Phuc Van Pham
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1083)

Abstract

Mesenchymal stem cell (MSC) transplantation is a novel treatment for diabetes mellitus, especially type 1 diabetes. Many recent publications have demonstrated the efficacy of MSC transplantation on reducing blood glucose and increasing insulin production in both preclinical and clinical trials. However, the investigation of grafted cell doses has been lacking. Therefore, this study aimed to evaluate the different doses of MSCs on treatment of type 1 diabetes in mouse models. MSCs were isolated and expanded from human adipose tissue. Streptozotocin (STZ)-induced diabetic mice were divided into two groups that were intravenously transfused with two different doses of human MSCs: 106 or 2.106 cells/mouse. After transplantation, both grafted and placebo mice were monitored weekly for their blood glucose levels, glucose and insulin tolerance, pancreatic structural changes, and insulin production for 56 days after transplantation. The results showed that the higher dose of MSCs (2.106 cells/mouse) remarkably reduced death rate. The death rates were 50%, 66%, and 0% in placebo group, low-dose (1.106 MSCs) group, and high-dose (2.106 MSCs) group, respectively, after 56 days of treatment. Moreover, blood glucose levels were lower for the high-dose group compared to other groups. Glucose and insulin tolerance, as well as insulin production, were significantly improved in mice transplanted with 2.106 cells. The histochemical analyses also support these results. Thus, a higher (e.g., 2.106) dose of MSCs may be an effective dose for treatment of type 1 diabetes mellitus.

Keywords

Diabetes mellitus Stem cells Adipose-derived stem cells Mesenchymal stem cells Cell dose Islet regeneration 

Abbreviations

hADSCs

Human adipose-derived stem cells

GTT

Glucose tolerance test

H&E

Hematoxylin and eosin

MSCs

Mesenchymal stem cells

STZ

Streptozotocin

Th1/Th2

T helper 1/T helper 2

TNF-α

Tumor necrosis factor-alpha

IL-10

Interleukin-10

IL-12

Interleukin-12

IFN-γ

Interferon-gamma

EGF

Epidermal growth factor

bFGF

Basic fibroblast growth factor

PDGF

Platelet-derived growth factor

TGF-β

Transforming growth factor-beta

VEGF

Vascular endothelial growth factor

HGF

Hepatocyte growth factor

IGF

Insulin growth factor-1

NO

Nitric oxide

PGE2

Prostaglandin E2

IDO

Indoleamine 2,3-dioxygenase

Notes

Acknowledgment

This research was funded by the Ministry of Science and Technology via project Grant No. DTDL.2012-G/23 and Vietnam National University, Ho Chi Minh City, via project No. C2016-18-18.

Author Contribution

LTTD, designed the study, performed the experiments, analyzed the data, and drafted the manuscript; PVP, KDT, designed the study and reviewed and corrected the manuscript; ANTB, CLTN, performed the experiments and analyzed the data and drafted the manuscript; NCT, ATVB, performed the experiments and reviewed and drafted the manuscript; and NPK analyzed the data and wrote the manuscript.

Competing Interests

The authors declare that no competing interests exist.

References

  1. Aghazadeh, Y., & Nostro, M. C. (2017). Cell therapy for type 1 diabetes: Current and future strategies. Current Diabetes Reports, 17, 37.CrossRefPubMedGoogle Scholar
  2. Atoui, R., & Chiu, R. C. (2012). Concise review: Immunomodulatory properties of mesenchymal stem cells in cellular transplantation: Update, controversies, and unknowns. Stem Cells Translational Medicine, 1, 200–205.CrossRefPubMedGoogle Scholar
  3. Bell, G. I., Broughton, H. C., Levac, K. D., Allan, D. A., Xenocostas, A., & Hess, D. A. (2012a). Transplanted human bone marrow progenitor subtypes stimulate endogenous islet regeneration and revascularization. Stem Cells and Development, 21, 97–109.CrossRefPubMedGoogle Scholar
  4. Bell, G. I., Meschino, M. T., Hughes-Large, J. M., Broughton, H. C., Xenocostas, A., & Hess, D. A. (2012b). Combinatorial human progenitor cell transplantation optimizes islet regeneration through secretion of paracrine factors. Stem Cells and Development, 21, 1863–1876.CrossRefPubMedGoogle Scholar
  5. Bhansali, S., Dutta, P., Kumar, V., Yadav, M. K., Jain, A., Mudaliar, S., Bhansali, S., Sharma, R. R., Jha, V., Marwaha, N., et al. (2017). Efficacy of autologous bone marrow-derived mesenchymal stem cell and mononuclear cell transplantation in type 2 diabetes mellitus: A randomized, placebo-controlled comparative study. Stem Cells and Development, 26, 471–481.CrossRefPubMedGoogle Scholar
  6. Cantu-Rodriguez, O. G., Lavalle-Gonzalez, F., Herrera-Rojas, M. A., Jaime-Perez, J. C., Hawing-Zarate, J. A., Gutierrez-Aguirre, C. H., Mancias-Guerra, C., Gonzalez-Llano, O., Zapata-Garrido, A., Villarreal-Perez, J. Z., et al. (2016). Long-term insulin independence in type 1 diabetes mellitus using a simplified autologous stem cell transplant. The Journal of Clinical Endocrinology and Metabolism, 101, 2141–2148.CrossRefPubMedGoogle Scholar
  7. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D., & Horwitz, E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8, 315–317.CrossRefGoogle Scholar
  8. Ezquer, F., Ezquer, M., Contador, D., Ricca, M., Simon, V., & Conget, P. (2012). 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.CrossRefPubMedGoogle Scholar
  9. Gabr, M. M., Zakaria, M. M., Refaie, A. F., Ismail, A. M., Abou-El-Mahasen, M. A., Ashamallah, S. A., Khater, S. M., El-Halawani, S. M., Ibrahim, R. Y., Uin, G. S., et al. (2013). Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice. Cell Transplantation, 22, 133–145.CrossRefPubMedGoogle Scholar
  10. Gao, F., Chiu, S. M., Motan, D. A., Zhang, Z., Chen, L., Ji, H. L., Tse, H. F., Fu, Q. L., & Lian, Q. (2016). Mesenchymal stem cells and immunomodulation: Current status and future prospects. Cell Death & Disease, 7, e2062.CrossRefGoogle Scholar
  11. Guariguata, L., Whiting, D. R., Hambleton, I., Beagley, J., Linnenkamp, U., & Shaw, J. E. (2014). Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Research and Clinical Practice, 103, 137–149.CrossRefPubMedGoogle Scholar
  12. Ho, J. H., Tseng, T. C., Ma, W. H., Ong, W. K., Chen, Y. F., Chen, M. H., Lin, M. W., Hong, C. Y., & Lee, O. K. (2012). Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and beta-cell differentiation in streptozocin-induced diabetic mice. Cell Transplantation, 21, 997–1009.CrossRefPubMedGoogle Scholar
  13. Hu, J., Wang, Y., Wang, F., Wang, L., Yu, X., Sun, R., Wang, Z., Wang, L., Gao, H., Fu, Z., et al. (2015). Effect and mechanisms of human Wharton’s jelly-derived mesenchymal stem cells on type 1 diabetes in NOD model. Endocrine, 48, 124–134.CrossRefPubMedGoogle Scholar
  14. Kadam, S. S., & Bhonde, R. R. (2010). Islet neogenesis from the constitutively nestin expressing human umbilical cord matrix derived mesenchymal stem cells. Islets, 2, 112–120.CrossRefPubMedGoogle Scholar
  15. Kao, S. Y., Shyu, J. F., Wang, H. S., Lin, C. H., Su, C. H., Chen, T. H., Weng, Z. C., & Tsai, P. J. (2015). Comparisons of differentiation potential in human mesenchymal stem cells from Wharton’s jelly, bone marrow, and pancreatic tissues. Stem Cells International, 2015, 306158.CrossRefPubMedGoogle Scholar
  16. Karnieli, O., Izhar-Prato, Y., Bulvik, S., & Efrat, S. (2007). Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation. Stem Cells, 25, 2837–2844.CrossRefPubMedGoogle Scholar
  17. Kono, T. M., Sims, E. K., Moss, D. R., Yamamoto, W., Ahn, G., Diamond, J., Tong, X., Day, K. H., Territo, P. R., Hanenberg, H., et al. (2014). Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia: Analysis of hASC-derived paracrine effectors. Stem Cells, 32, 1831–1842.CrossRefPubMedGoogle Scholar
  18. Lee, R. H., Seo, M. J., Reger, R. L., Spees, J. L., Pulin, A. A., Olson, S. D., & Prockop, D. J. (2006). Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proceedings of the National Academy of Sciences of the United States of America, 103, 17438–17443.CrossRefPubMedGoogle Scholar
  19. Li, L., Shen, S., Ouyang, J., Hu, Y., Hu, L., Cui, W., Zhang, N., Zhuge, Y. Z., Chen, B., Xu, J., et al. (2012). Autologous hematopoietic stem cell transplantation modulates immunocompetent cells and improves beta-cell function in Chinese patients with new onset of type 1 diabetes. The Journal of Clinical Endocrinology and Metabolism, 97, 1729–1736.CrossRefGoogle Scholar
  20. Ma, O. K., & Chan, K. H. (2016). Immunomodulation by mesenchymal stem cells: Interplay between mesenchymal stem cells and regulatory lymphocytes. World Journal of Stem Cells, 8, 268–278.CrossRefPubMedGoogle Scholar
  21. Marappagounder, D., Somasundaram, I., Dorairaj, S., & Sankaran, R. J. (2013). Differentiation of mesenchymal stem cells derived from human bone marrow and subcutaneous adipose tissue into pancreatic islet-like clusters in vitro. Cellular & Molecular Biology Letters, 18, 75–88.CrossRefGoogle Scholar
  22. Meyerrose, T. E., De Ugarte, D. A., Hofling, A. A., Herrbrich, P. E., Cordonnier, T. D., Shultz, L. D., Eagon, J. C., Wirthlin, L., Sands, M. S., Hedrick, M. A., et al. (2007). In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells, 25, 220–227.CrossRefPubMedGoogle Scholar
  23. Mohammadi Ayenehdeh, J., Niknam, B., Rasouli, S., Hashemi, S. M., Rahavi, H., Rezaei, N., Soleimani, M., Liaeiha, A., Niknam, M. H., & Tajik, N. (2017). Immunomodulatory and protective effects of adipose tissue-derived mesenchymal stem cells in an allograft islet composite transplantation for experimental autoimmune type 1 diabetes. Immunology Letters, 188, 21–31.CrossRefPubMedGoogle Scholar
  24. Moshtagh, P. R., Emami, S. H., & Sharifi, A. M. (2013). Differentiation of human adipose-derived mesenchymal stem cell into insulin-producing cells: An in vitro study. Journal of Physiology and Biochemistry, 69, 451–458.CrossRefPubMedGoogle Scholar
  25. Nagaishi, K., Mizue, Y., Chikenji, T., Otani, M., Nakano, M., Konari, N., & Fujimiya, M. (2016). Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Scientific Reports, 6, 34842.CrossRefPubMedGoogle Scholar
  26. Okura, H., Komoda, H., Fumimoto, Y., Lee, C. M., Nishida, T., Sawa, Y., & Matsuyama, A. (2009). Transdifferentiation of human adipose tissue-derived stromal cells into insulin-producing clusters. Journal of Artificial Organs, 12, 123–130.CrossRefPubMedGoogle Scholar
  27. Pham, V. P., Vu, B. N., Phan, L. C. N., Le, M. D., Truong, C. N., Truong, H. N., Bui, H. T. K., & Phan, K. N. (2014). Good manufacturing practice-compliant isolation and culture of human adipose-derived stem cells. Biomedical Research and Therapy, 1, 133–141.Google Scholar
  28. Rahavi, H., Hashemi, S. M., Soleimani, M., Mohammadi, J., & Tajik, N. (2015). Adipose tissue-derived mesenchymal stem cells exert in vitro immunomodulatory and beta cell protective functions in streptozotocin-induced diabetic mice model. Journal of Diabetes Research, 2015, 878535.CrossRefPubMedGoogle Scholar
  29. Seyedi, F., Farsinejad, A., Nematollahi-Mahani, S. A., Eslaminejad, T., & Nematollahi-Mahani, S. N. (2016). Suspension culture alters insulin secretion in induced human umbilical cord matrix-derived mesenchymal cells. Cell Journal, 18, 52–61.PubMedGoogle Scholar
  30. Sood, V., Bhansali, A., Mittal, B. R., Singh, B., Marwaha, N., Jain, A., & Khandelwal, N. (2017). Autologous bone marrow derived stem cell therapy in patients with type 2 diabetes mellitus – defining adequate administration methods. World Journal of Diabetes, 8, 381–389.CrossRefPubMedGoogle Scholar
  31. Sordi, V., Melzi, R., Mercalli, A., Formicola, R., Doglioni, C., Tiboni, F., Ferrari, G., Nano, R., Chwalek, K., Lammert, E., et al. (2010). Mesenchymal cells appearing in pancreatic tissue culture are bone marrow-derived stem cells with the capacity to improve transplanted islet function. Stem Cells, 28, 140–151.CrossRefPubMedGoogle Scholar
  32. Spaggiari, G. M., Capobianco, A., Abdelrazik, H., Becchetti, F., Mingari, M. C., & Moretta, L. (2008). Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: Role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood, 111, 1327–1333.CrossRefPubMedGoogle Scholar
  33. Thi-Tung Dang, L., Nguyen-Tu Bui, A., Minh Pham, V., Kim Phan, N., & Van Pham, P. (2015). Production of islet-like insulin-producing cell clusters in vitro from adipose derived stem cells. Biomedical Research and Therapy, 2, 184–192.Google Scholar
  34. Tsai, P. J., Wang, H. S., Lin, G. J., Chou, S. C., Chu, T. H., Chuan, W. T., Lu, Y. J., Weng, Z. C., Su, C. H., Hsieh, P. S., et al. (2015). Undifferentiated Wharton’s jelly mesenchymal stem cell transplantation induces insulin-producing cell differentiation and suppression of T-cell-mediated autoimmunity in nonobese diabetic mice. Cell Transplantation, 24, 1555–1570.CrossRefPubMedGoogle Scholar
  35. Van Pham, P., Thi-My Nguyen, P., Thai-Quynh Nguyen, A., Minh Pham, V., Nguyen-Tu Bui, A., Thi-Tung Dang, L., Gia Nguyen, K., & Kim Phan, N. (2014). Improved differentiation of umbilical cord blood-derived mesenchymal stem cells into insulin-producing cells by PDX-1 mRNA transfection. Differentiation, 87, 200–208.CrossRefPubMedGoogle Scholar
  36. Wehbe, T., Chahine, N. A., Sissi, S., Abou-Joaude, I., & Chalhoub, L. (2016). Bone marrow derived stem cell therapy for type 2 diabetes mellitus. Stem Cell Investigation, 3, 87.CrossRefPubMedGoogle Scholar
  37. Yaochite, J. N., de Lima, K. W., Caliari-Oliveira, C., Palma, P. V., Couri, C. E., Simoes, B. P., Covas, D. T., Voltarelli, J. C., Oliveira, M. C., Donadi, E. A., et al. (2016). Multipotent mesenchymal stromal cells from patients with newly diagnosed type 1 diabetes mellitus exhibit preserved in vitro and in vivo immunomodulatory properties. Stem Cell Research & Therapy, 7, 14.CrossRefGoogle Scholar
  38. Ye, L., Li, L., Wan, B., Yang, M., Hong, J., Gu, W., Wang, W., & Ning, G. (2017). Immune response after autologous hematopoietic stem cell transplantation in type 1 diabetes mellitus. Stem Cell Research & Therapy, 8, 90.CrossRefGoogle Scholar
  39. Youssef, A., Aboalola, D., & Han, V. K. (2017). The roles of insulin-like growth factors in mesenchymal stem cell niche. Stem Cells International, 2017, 9453108.PubMedGoogle Scholar
  40. Zhou, Y., Hu, Q., Chen, F., Zhang, J., Guo, J., Wang, H., Gu, J., Ma, L., & Ho, G. (2015). Human umbilical cord matrix-derived stem cells exert trophic effects on beta-cell survival in diabetic rats and isolated islets. Disease Models & Mechanisms, 8, 1625–1633.CrossRefGoogle Scholar
  41. Zhou, J. Y., Zhang, Z., & Qian, G. S. (2016). Mesenchymal stem cells to treat diabetic neuropathy: A long and strenuous way from bench to the clinic. Cell Death Discovery, 2, 16055.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Loan Thi-Tung Dang
    • 1
  • Anh Nguyen-Tu Bui
    • 1
  • Cong Le-Thanh Nguyen
    • 1
    • 2
  • Nhat Chau Truong
    • 1
    • 2
  • Anh Thi-Van Bui
    • 1
    • 2
  • Ngoc Phan Kim
    • 1
  • Kiet Dinh Truong
    • 3
  • Phuc Van Pham
    • 1
    • 2
  1. 1.Stem Cell InstituteUniversity of Science, VNUHCMHo Chi Minh cityVietnam
  2. 2.Laboratory of Stem Cell Research and ApplicationUniversity of Science, VNUHCMHo Chi Minh cityVietnam
  3. 3.Medical Genetics InstituteHo Chi Minh cityVietnam

Personalised recommendations