Mesenchymal stem cells for diabetes mellitus treatment: new advances

Main Article Content

Loan Thi-Tung Dang Ngoc Kim Phan Kiet Dinh Truong


Mesenchymal stem cells (MSCs) are the most widely used stem cells of the human body due to ease of successful isolation and expansion for many years. In particular, from 2012 until now, MSCs have been widely clinically used to treat various diseases, including graft versus host disease (GVHD), Crohn’s disease, and knee osteoarthritis. In this review, the applications of MSCs in diabetes will be reviewed and discussed. Diabetes mellitus type 1, also known as Type 1 diabetes (T1DM), is an autoimmune disease in which immune cells attack the beta cells in islets of Langerhans (pancreatic islets). Although type 2 diabetes (T2DM) is considered to be a disease related to insulin resistance, several recent studies have shown some relation of immune dysfunction in this disease. Therefore, MSC transplantation may be a beneficial treatment for both T1DM and T2DM. MSC transplantation in preclinical trials and clinical trials for T1DM and T2DM have shown a moderate to significant improvement in diabetes without adverse side effects. In this review, we will discuss some of the updates from preclinical and clinical trials of MSC transplantation for diabetes.


Ammar, H.I., Sequiera, G.L., Nashed, M.B., Ammar, R.I., Gabr, H.M., Elsayed, H.E., Sareen, N., Rub, E.A., Zickri, M.B., and Dhingra, S. (2015). Comparison of adipose tissue- and bone marrow- derived mesenchymal stem cells for alleviating doxorubicin-induced cardiac dysfunction in diabetic rats. Stem cell research & therapy 6, 148.
Atoui, R., and 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.
Bastaki, S. (2005). Diabetes mellitus and its treatment. Int J Diabetes & Metabolism 13, 111-134.
Chao, K.C., Chao, K.F., Fu, Y.S., and Liu, S.H. (2008). Islet-like clusters derived from mesenchymal stem cells in Wharton's Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PloS one 3, e1451.
Cheng, N.C., Hsieh, T.Y., Lai, H.S., and Young, T.H. (2016). High glucose-induced reactive oxygen species generation promotes stemness in human adipose-derived stem cells. Cytotherapy 18, 371-383.
Cianfarani, F., Toietta, G., Di Rocco, G., Cesareo, E., Zambruno, G., and Odorisio, T. (2013). Diabetes impairs adipose tissue-derived stem cell function and efficiency in promoting wound healing. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 21, 545-553.
Corcione, A., Benvenuto, F., Ferretti, E., Giunti, D., Cappiello, V., Cazzanti, F., Risso, M., Gualandi, F., Mancardi, G.L., Pistoia, V., et al. (2006). Human mesenchymal stem cells modulate B-cell functions. Blood 107, 367-372.
Cramer, C., Freisinger, E., Jones, R.K., Slakey, D.P., Dupin, C.L., Newsome, E.R., Alt, E.U., and Izadpanah, R. (2010). Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells. Stem cells and development 19, 1875-1884.
Dave, S.D., Trivedi, H.L., Gopal, S.C., and Chandra, T. (2014). Combined therapy of insulin-producing cells and haematopoietic stem cells offers better diabetic control than only haematopoietic stem cells' infusion for patients with insulin-dependent diabetes. BMJ case reports 2014.
Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D., and Horwitz, E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315-317.
Dong, Q.Y., Chen, L., Gao, G.Q., Wang, L., Song, J., Chen, B., Xu, Y.X., and Sun, L. (2008). Allogeneic diabetic mesenchymal stem cells transplantation in streptozotocin-induced diabetic rat. Clinical and investigative medicine Medecine clinique et experimentale 31, E328-337.
Ducret, M., Fabre, H., Degoult, O., Atzeni, G., McGuckin, C., Forraz, N., Mallein-Gerrin, F., Perrier-Groult, E., and Fargues, J.C. (2016). A standardized procedure to obtain mesenchymal stem/stromal cells from minimally manipulated dental pulp and Wharton's jelly samples. Bulletin du Groupement international pour la recherche scientifique en stomatologie & odontologie 53, e37.
Ezquer, M. (2014). Mesenchymal Stem Cell Therapy in Type 1 Diabetes Mellitus and Its Main Complications: From Experimental Findings to Clinical Practice. Journal of Stem Cell Research & Therapy 04.
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.
Gao, X., Song, L., Shen, K., Wang, H., Qian, M., Niu, W., and Qin, X. (2014). Bone marrow mesenchymal stem cells promote the repair of islets from diabetic mice through paracrine actions. Molecular and cellular endocrinology 388, 41-50.
Halban, P.A. (2004). Cellular sources of new pancreatic beta cells and therapeutic implications for regenerative medicine. Nature cell biology 6, 1021-1025.
Hankamolsiri, W., Manochantr, S., Tantrawatpan, C., Tantikanlayaporn, D., Tapanadechopone, P., and Kheolamai, P. (2016). The Effects of High Glucose on Adipogenic and Osteogenic Differentiation of Gestational Tissue-Derived MSCs. Stem cells international 2016, 9674614.
Hess, D., Li, L., Martin, M., Sakano, S., Hill, D., Strutt, B., Thyssen, S., Gray, D.A., and Bhatia, M. (2003). Bone marrow-derived stem cells initiate pancreatic regeneration. Nature biotechnology 21, 763-770.
Ho, J.H., Tseng, T.C., Ma, W.H., Ong, W.K., Chen, Y.F., Chen, M.H., Lin, M.W., Hong, C.Y., and 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.
Hu, J., Wang, F., Sun, R., Wang, Z., Yu, X., Wang, L., Gao, H., Zhao, W., Yan, S., and Wang, Y. (2014). Effect of combined therapy of human Wharton's jelly-derived mesenchymal stem cells from umbilical cord with sitagliptin in type 2 diabetic rats. Endocrine 45, 279-287.
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.
Hu, Y.H., Wu, D.Q., Gao, F., Li, G.D., Yao, L., and Zhang, X.C. (2009). A secretory function of human insulin-producing cells in vivo. Hepatobiliary & pancreatic diseases international : HBPD INT 8, 255-260.
IDF (2015). IDF Diabetes atlas Edition 7.
Jiang, X.X., Zhang, Y., Liu, B., Zhang, S.X., Wu, Y., Yu, X.D., and Mao, N. (2005). Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105, 4120-4126.
Kadam, S.S., Sudhakar, M., Nair, P.D., and Bhonde, R.R. (2010). Reversal of experimental diabetes in mice by transplantation of neo-islets generated from human amnion-derived mesenchymal stromal cells using immuno-isolatory macrocapsules. Cytotherapy 12, 982-991.
Kao, S.Y., Shyu, J.F., Wang, H.S., Lin, C.H., Su, C.H., Chen, T.H., Weng, Z.C., and 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.
Kim, H., Han, J.W., Lee, J.Y., Choi, Y.J., Sohn, Y.D., Song, M., and Yoon, Y.S. (2015). Diabetic Mesenchymal Stem Cells Are Ineffective for Improving Limb Ischemia Due to Their Impaired Angiogenic Capability. Cell transplantation 24, 1571-1584.
Kim, J., Park, S., Kang, H.M., Ahn, C.W., Kwon, H.C., Song, J.H., Lee, Y.J., Lee, K.H., Yang, H., Baek, S.Y., et al. (2012). Human insulin secreted from insulinogenic xenograft restores normoglycemia in type 1 diabetic mice without immunosuppression. Cell transplantation 21, 2131-2147.
Kong, D., Zhuang, X., Wang, D., Qu, H., Jiang, Y., Li, X., Wu, W., Xiao, J., Liu, X., Liu, J., et al. (2014). Umbilical cord mesenchymal stem cell transfusion ameliorated hyperglycemia in patients with type 2 diabetes mellitus. Clinical laboratory 60, 1969-1976.
Le, P.T.-B., Van Pham, P., Vu, N.B., Dang, L.T.-T., and Phan, N.K. (2016). Expanded autologous adipose derived stem cell transplantation for type 2 diabetes mellitus. Biomedical Research and Therapy 3, 1034-1044.
Lee, R.H., Seo, M.J., Reger, R.L., Spees, J.L., Pulin, A.A., Olson, S.D., and 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.
Liu, X., Zheng, P., Wang, X., Dai, G., Cheng, H., Zhang, Z., Hua, R., Niu, X., Shi, J., and An, Y. (2014). A preliminary evaluation of efficacy and safety of Wharton's jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus. Stem cell research & therapy 5, 57.
Luz-Crawford, P., Kurte, M., Bravo-Alegria, J., Contreras, R., Nova-Lamperti, E., Tejedor, G., Noel, D., Jorgensen, C., Figueroa, F., Djouad, F., et al. (2013). Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem cell research & therapy 4, 65.
Ma, S., Xie, N., Li, W., Yuan, B., Shi, Y., and Wang, Y. (2014). Immunobiology of mesenchymal stem cells. Cell death and differentiation 21, 216-225.
Mattar, P., and Bieback, K. (2015). Comparing the Immunomodulatory Properties of Bone Marrow, Adipose Tissue, and Birth-Associated Tissue Mesenchymal Stromal Cells. Frontiers in immunology 6, 560.
Menard, C., Pacelli, L., Bassi, G., Dulong, J., Bifari, F., Bezier, I., Zanoncello, J., Ricciardi, M., Latour, M., Bourin, P., et al. (2013). Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls. Stem cells and development 22, 1789-1801.
Montanucci, P., Pescara, T., Pennoni, I., Alunno, A., Bistoni, O., Torlone, E., Luca, G., Gerli, R., Basta, G., and Calafiore, R. (2016). Functional Profiles of Human Umbilical Cord-Derived Adult Mesenchymal Stem Cells in Obese/Diabetic Versus Healthy Women. Current diabetes reviews.
Moorefield, E.C. (2012). Stem cell-based regenerative pharmacology for the treatment ò diabetes mellitus.
Nauta, A.J., and Fibbe, W.E. (2007). Immunomodulatory properties of mesenchymal stromal cells. Blood 110, 3499-3506.
Ngoc, P.K., Phuc, P.V., Nhung, T.H., Thuy, D.T., and Nguyet, N.T. (2011). Improving the efficacy of type 1 diabetes therapy by transplantation of immunoisolated insulin-producing cells. Human cell 24, 86-95.
Phadnis, S.M., Ghaskadbi, S.M., Hardikar, A.A., and Bhonde, R.R. (2009). Mesenchymal stem cells derived from bone marrow of diabetic patients portrait unique markers influenced by the diabetic microenvironment. The review of diabetic studies : RDS 6, 260-270.
Pham, P.V., Vu, N.B., Pham, V.M., Truong, N.H., Pham, T.L., Dang, L.T., Nguyen, T.T., Bui, A.N., and Phan, N.K. (2014). Good manufacturing practice-compliant isolation and culture of human umbilical cord blood-derived mesenchymal stem cells. Journal of translational medicine 12, 56.
Ren, H., Sang, Y., Zhang, F., Liu, Z., Qi, N., and Chen, Y. (2016). Comparative Analysis of Human Mesenchymal Stem Cells from Umbilical Cord, Dental Pulp, and Menstrual Blood as Sources for Cell Therapy. Stem cells international 2016, 3516574.
Sensebe, L., Bourin, P., and Tarte, K. (2011). Good manufacturing practices production of mesenchymal stem/stromal cells. Human gene therapy 22, 19-26.
Seyedi, F., Farsinejad, A., Moshrefi, M., and Nematollahi-Mahani, S.N. (2015). In vitro evaluation of different protocols for the induction of mesenchymal stem cells to insulin-producing cells. In vitro cellular & developmental biology Animal 51, 866-878.
Seyedi, F., Farsinejad, A., Nematollahi-Mahani, S.A., Eslaminejad, T., and Nematollahi-Mahani, S.N. (2016). Suspension Culture Alters Insulin Secretion in Induced Human Umbilical Cord Matrix-Derived Mesenchymal Cells. Cell journal 18, 52-61.
Si, Y., Zhao, Y., Hao, H., Liu, J., Guo, Y., Mu, Y., Shen, J., Cheng, Y., Fu, X., and Han, W. (2012). Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity. Diabetes 61, 1616-1625.
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.
Spaggiari, G.M., Capobianco, A., Abdelrazik, H., Becchetti, F., Mingari, M.C., and 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.
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.
Tobita, M., Tajima, S., and Mizuno, H. (2015). Adipose tissue-derived mesenchymal stem cells and platelet-rich plasma: stem cell transplantation methods that enhance stemness. Stem cell research & therapy 6, 215.
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.
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., and Kim Phan, N. (2014). Improved differentiation of umbilical cord blood-derived mesenchymal stem cells into insulin-producing cells by PDX-1 mRNA transfection. Differentiation; research in biological diversity 87, 200-208.
Van Pham, P., Vu, N.B., and Phan, N.K. (2016). Umbilical cord-derived stem cells (MODULATISTTM) show strong immunomodulation capacity compared to adipose tissue-derived or bone marrow-derived mesenchymal stem cells. Biomedical Research and Therapy 3, 687-696.
Voltarelli, J.C., Couri, C.E., Rodrigues, M.C., Moraes, D.A., Stracieri, A.B., Pieroni, F., Navarro, G., Leal, A.M., and Simoes, B.P. (2011). Stem cell therapies for type 1 diabetes mellitus. Indian journal of experimental biology 49, 395-400.
Wajid, N., Naseem, R., Anwar, S.S., Awan, S.J., Ali, M., Javed, S., and Ali, F. (2015). The effect of gestational diabetes on proliferation capacity and viability of human umbilical cord-derived stromal cells. Cell and tissue banking 16, 389-397.
Wang, Y., Chen, X., Cao, W., and Shi, Y. (2014). Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nature immunology 15, 1009-1016.
Wehner, R., Taubert, C., Mende, T., Gaebler, C., de Andrade, A.V., Bornhauser, M., Werner, C., Tonn, T., Schakel, K., Bachmann, M., et al. (2013). Engineered extracellular matrix components do not alter the immunomodulatory properties of mesenchymal stromal cells in vitro. Journal of tissue engineering and regenerative medicine 7, 921-924.
Wu, C., Liu, F., Li, P., Zhao, G., Lan, S., Jiang, W., Meng, X., Tian, L., Li, G., Li, Y., et al. (2015). Engineered hair follicle mesenchymal stem cells overexpressing controlled-release insulin reverse hyperglycemia in mice with type L diabetes. Cell transplantation 24, 891-907.
Wu, X.H., Liu, C.P., Xu, K.F., Mao, X.D., Zhu, J., Jiang, J.J., Cui, D., Zhang, M., Xu, Y., and Liu, C. (2007). Reversal of hyperglycemia in diabetic rats by portal vein transplantation of islet-like cells generated from bone marrow mesenchymal stem cells. World journal of gastroenterology 13, 3342-3349.
Xiao, N., Zhao, X., Luo, P., Guo, J., Zhao, Q., Lu, G., and Cheng, L. (2013). Co-transplantation of mesenchymal stromal cells and cord blood cells in treatment of diabetes. Cytotherapy 15, 1374-1384.
Xie, Z., Hao, H., Tong, C., Cheng, Y., Liu, J., Pang, Y., Si, Y., Guo, Y., Zang, L., Mu, Y., et al. (2016). Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats. Stem cells 34, 627-639.
Xin, Y., Jiang, X., Wang, Y., Su, X., Sun, M., Zhang, L., Tan, Y., Wintergerst, K.A., Li, Y., and Li, Y. (2016). Insulin-Producing Cells Differentiated from Human Bone Marrow Mesenchymal Stem Cells In Vitro Ameliorate Streptozotocin-Induced Diabetic Hyperglycemia. PloS one 11, e0145838.
Yang, Z., Li, K., Yan, X., Dong, F., and Zhao, C. (2010). Amelioration of diabetic retinopathy by engrafted human adipose-derived mesenchymal stem cells in streptozotocin diabetic rats. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 248, 1415-1422.
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.
Zhang, L., Gianani, R., Nakayama, M., Liu, E., Kobayashi, M., Baschal, E., Yu, L., Babu, S., Dawson, A., Johnson, K., et al. (2008). Type 1 diabetes: chronic progressive autoimmune disease. Novartis Foundation symposium 292, 85-94; discussion 94-88, 122-129, 202-123.
Zhang, Y., and Dou, Z. (2014). Under a nonadherent state, bone marrow mesenchymal stem cells can be efficiently induced into functional islet-like cell clusters to normalize hyperglycemia in mice: a control study. Stem cell research & therapy 5, 66.
Zhang, Y., Shen, W., Hua, J., Lei, A., Lv, C., Wang, H., Yang, C., Gao, Z., and Dou, Z. (2010). Pancreatic islet-like clusters from bone marrow mesenchymal stem cells of human first-trimester abortus can cure streptozocin-induced mouse diabetes. Rejuvenation research 13, 695-706.
Zhao, S., Wehner, R., Bornhauser, M., Wassmuth, R., Bachmann, M., and Schmitz, M. (2010). Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem cells and development 19, 607-614.
Zhou, H., Tian, H.M., Long, Y., Zhang, X.X., Zhong, L., Deng, L., Chen, X.H., and Li, X.Q. (2009). Mesenchymal stem cells transplantation mildly ameliorates experimental diabetic nephropathy in rats. Chinese medical journal 122, 2573-2579.
Zhou, Y., Hu, Q., Chen, F., Zhang, J., Guo, J., Wang, H., Gu, J., Ma, L., and 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.


Download data is not yet available.

Article Details

How to Cite
DANG, Loan Thi-Tung; PHAN, Ngoc Kim; TRUONG, Kiet Dinh. Mesenchymal stem cells for diabetes mellitus treatment: new advances. Biomedical Research and Therapy, [S.l.], v. 4, n. 1, p. 1062-1081, jan. 2017. ISSN 2198-4093. Available at: <>. Date accessed: 14 dec. 2017. doi:

Most read articles by the same author(s)