Diabetes mellitus (DM) is a group of metabolic diseases in which a person has high blood glucose levels resulting from defects in insulin secretion and insulin action. The chronic hyperglycemia damages the eyes, kidneys, nerves, heart, and blood vessels. Curative therapies mainly include diet, insulin, and oral hypoglycemic agents. However, these therapies fail to maintain blood glucose levels in the normal range all the time. Although pancreas or islet-cell transplantation achieves better glucose control, a major obstacle is the shortage of donor organs. Recently, research has focused on stem cells which can be classified into embryonic stem cells (ESCs) and tissue stem cells (TSCs) to generate functional β cells. TSCs include the bone-marrow-, liver-, and pancreas-derived stem cells. In this review, we focus on treatment using bone marrow stem cells for type 1 and 2 DM. 1. Introduction Diabetes mellitus (DM) is a devastating disease [1] that includes 2 main types: type 1 and type 2 DM. DM therapies mainly include diet, insulin, oral hypoglycemic agents, and pancreas or islet-cell transplantation. Exogenous insulin replacement has been the primary therapeutic technique for controlling plasma glucose levels. However, because of the shortage of donor organs, recent research has focused on stem cells, including pancreatic stem cells, hepatic stem cells, bone marrow stem cells (BMSCs), induced pluripotent stem cells (iPS), and embryonic stem cells (ESCs) to generate β cells for DM treatment [2]. BM is an invaluable source of adult pluripotent stem cells, and this review focuses on the treatment of DM using BMSCs. 2. Pathophysiology of Type 1 DM Type 1 DM is a T-cell-mediated autoimmune disease accompanying lymphocytic infiltration of the pancreatic islets. The nonobese diabetic (NOD) mouse is a spontaneous mouse model of type 1 DM and involves many of the same autoantigens targeted by human T cells [3, 4]. BM-derived T-cell precursors go to the thymus to differentiate into mature T cells via positive and negative selection. Thymocytes expressing TCRs recognize self-antigen-MHC complexes with high affinity/avidity undergoing central deletion. In contrast, thymocytes expressing low-affinity TCRs for the same complexes differentiate into mature T cells and populate the peripheral lymphoid organs where they become available for recognizing foreign antigens [5]. Autoreactive T cells, with their relatively high avidity and pathogenic potential, can escape thymocyte negative selection and elicit autoimmunity in the absence of adequate peripheral regulation [6].
References
[1]
American Diabetes Association, “Diagnosis and classification of diabetes mellitus,” Diabetes Care, vol. 27, supplement 1, pp. S5–S10, 2004.
[2]
M. A. Hussain and N. D. Theise, “Stem-cell therapy for diabetes mellitus,” The Lancet, vol. 364, no. 9429, pp. 203–209, 2004.
[3]
T. L. Delovitch and B. Singh, “The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD,” Immunity, vol. 7, pp. 727–738, 1997.
[4]
M. A. Atkinson and E. H. Leiter, “The NOD mouse model of type 1 diabetes: as good as it gets?” Nature Medicine, vol. 5, no. 6, pp. 601–604, 1999.
[5]
P. Marrack and D. C. Parker, “A little of what you fancy,” Nature, vol. 368, no. 6470, pp. 397–398, 1994.
[6]
B. Han, P. Serra, J. Yamanouchi et al., “Developmental control of CD8+ T cell-avidity maturation in autoimmune diabetes,” Journal of Clinical Investigation, vol. 115, no. 7, pp. 1879–1887, 2005.
[7]
J. M. Gardner, A. L. Fletcher, M. S. Anderson, and S. J. Turley, “AIRE in the thymus and beyond,” Current Opinion in Immunology, vol. 21, no. 6, pp. 582–589, 2009.
[8]
P. Vafiadis, S. T. Bennett, J. A. Todd et al., “Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus,” Nature Genetics, vol. 15, no. 3, pp. 289–292, 1997.
[9]
D. V. Serreze, H. D. Chapman, D. S. Varnum et al., “B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu null mice,” Journal of Experimental Medicine, vol. 184, no. 5, pp. 2049–2053, 1996.
[10]
M. Akashi, S. Nagafuchi, K. Anzai et al., “Direct evidence for the contribution of B cells to the progression of insulitis and the development of diabetes in non-obese diabetic mice,” International Immunology, vol. 9, no. 8, pp. 1159–1164, 1997.
[11]
C. Y. Hu, D. Rodriguez-Pinto, W. Du et al., “Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice,” Journal of Clinical Investigation, vol. 117, no. 12, pp. 3857–3867, 2007.
[12]
L. J. Yang, “Liver stem cell-derived β-cell surrogates for treatment of type 1 diabetes,” Autoimmunity Reviews, vol. 5, no. 6, pp. 409–413, 2006.
[13]
X. Xu, J. D'Hoker, G. Stangé et al., “β cells can be generated from endogenous progenitors in injured adult mouse pancreas,” Cell, vol. 132, no. 2, pp. 197–207, 2008.
[14]
Z. Alipio, W. Liao, E. J. Roemer et al., “Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic β-like cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 30, pp. 13426–13431, 2010.
[15]
H. Segev, B. Fishman, A. Ziskind, M. Shulman, and J. Itskovitz-Eldor, “Differentiation of human embryonic stem cells into insulin-producing clusters,” Stem Cells, vol. 22, no. 3, pp. 265–274, 2004.
[16]
G. K. C. Brolén, N. Heins, J. Edsbagge, and H. Semb, “Signals from the embryonic mouse pancreas induce differentiation of human embryonic stem cells into insulin-producing β-cell-like cells,” Diabetes, vol. 54, no. 10, pp. 2867–2874, 2005.
[17]
M. F. Pittenger, A. M. Mackay, S. C. Beck et al., “Multilineage potential of adult human mesenchymal stem cells,” Science, vol. 284, no. 5411, pp. 143–147, 1999.
[18]
D. C. Colter, R. Class, C. M. DiGirolamo, and D. J. Prockop, “Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 7, pp. 3213–3218, 2000.
[19]
C. P. Khoo, P. Pozzilli, and M. R. Alison, “Endothelial progenitor cells and their potential therapeutic applications,” Regenerative Medicine, vol. 3, no. 6, pp. 863–876, 2008.
[20]
A. Ianus, G. G. Holz, N. D. Theise, and M. A. Hussain, “In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion,” Journal of Clinical Investigation, vol. 111, no. 6, pp. 843–850, 2003.
[21]
S. Ikehara, H. Ohtsuki, and R. A. Good, “Prevention of type I diabetes in nonobese diabetic mice by allogeneic bone marrow transplantation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 22, pp. 7743–7747, 1985.
[22]
Y. Hasegawa, T. Ogihara, T. Yamada et al., “Bone marrow (BM) transplantation promotes β-cell regeneration after acute injury through BM cell mobilization,” Endocrinology, vol. 148, no. 5, pp. 2006–2015, 2007.
[23]
R. Yasumizu, K. Sugiura, H. Iwai et al., “Treatment of type 1 diabetes mellitus in non-obese diabetic mice by transplantation of allogeneic bone marrow and pancreatic tissue,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 18, pp. 6555–6557, 1987.
[24]
H. Iwai, R. Yasumizu, K. Sugiura et al., “Successful pancreatic allografts in combination with bone marrow transplantation in mice,” Immunology, vol. 62, no. 3, pp. 457–462, 1987.
[25]
M. Taira, M. Inaba, K. Takada et al., “Treatment of streptozotocin-induced diabetes mellitus in rats by transplantation of islet cells from two major histocompatibility complex disparate rats in combination with intra bone marrow injection of allogenic bone marrow cells,” Transplantation, vol. 79, no. 6, pp. 680–687, 2005.
[26]
H. Cheng, Y. C. Zhang, S. Wolfe, et al., “Combinatorial treatment of bone marrow stem cells and stromal cell-derived factor 1 improves glycemia and insulin production in diabetic mice,” Molecular and Cellular Endocrinology, vol. 345, pp. 88–96, 2011.
[27]
M. M. Gabr, M. M. Zakaria, A. F. Refaie, et al., “Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice,” Cell Transplant. In press.
[28]
R. H. Lee, M. J. Seo, R. L. Reger et al., “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, vol. 103, no. 46, pp. 17438–17443, 2006.
[29]
V. S. Urbán, J. Kiss, J. Kovács et al., “Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes,” Stem Cells, vol. 26, no. 1, pp. 244–253, 2008.
[30]
P. Fiorina, M. Jurewicz, A. Augello et al., “Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes,” Journal of Immunology, vol. 183, no. 2, pp. 993–1004, 2009.
[31]
F. Ezquer, M. Ezquer, V. Simon, and P. Conget, “The antidiabetic effect of MSCs is not impaired by insulin prophylaxis and is not improved by a second dose of cells,” PLoS ONE, vol. 6, no. 1, Article ID e16566, 2011.
[32]
A. Milanesi, J. W. Lee, Z. Li, et al., “beta-Cell regeneration mediated by human bone marrow mesenchymal stem cells,” PLoS ONE, vol. 7, Article ID e42177, 2012.
[33]
A. Oikawa, M. Siragusa, F. Quaini, et al., “Diabetes mellitus induces bone marrow microangiopathy,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, pp. 498–508, 2010.
[34]
C. J. M. Loomans, E. J. P. De Koning, F. J. T. Staal et al., “Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes,” Diabetes, vol. 53, no. 1, pp. 195–199, 2004.
[35]
O. M. Tepper, R. D. Galiano, J. M. Capla et al., “Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures,” Circulation, vol. 106, no. 22, pp. 2781–2786, 2002.
[36]
V. Mathews, P. T. Hanson, E. Ford, J. Fujita, K. S. Polonsky, and T. A. Graubert, “Recruitment of bone marrow-derived endothelial cells to sites of pancreatic beta-cell injury,” Diabetes, vol. 53, no. 1, pp. 91–98, 2004.
[37]
G. P. Duffy, T. Ahsan, T. O'Brien, F. Barry, and R. M. Nerem, “Bone marrow-derived mesenchymal stem cells promote angiogenic processes in a time- and dose-dependent manner in vitro,” Tissue Engineering A, vol. 15, no. 9, pp. 2459–2470, 2009.
[38]
K. Tamama, C. K. Sen, and A. Wells, “Differentiation of bone marrow mesenchymal stem cells into the smooth muscle lineage by blocking ERK/MAPK signaling pathway,” Stem Cells and Development, vol. 17, no. 5, pp. 897–908, 2008.
[39]
W. M. Yue, W. Liu, Y. W. Bi et al., “Mesenchymal stem cells differentiate into an endothelial phenotype, reduce neointimal formation, and enhance endothelial function in a rat vein grafting model,” Stem Cells and Development, vol. 17, no. 4, pp. 785–793, 2008.
[40]
Z. Gong and L. E. Niklason, “Small-diameter human vessel wall engineered from bone marrow-derived mesenchymal stem cells (hMSCs),” The FASEB Journal, vol. 22, no. 6, pp. 1635–1648, 2008.
[41]
H. C. Quevedo, K. E. Hatzistergos, B. N. Oskouei et al., “Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 33, pp. 14022–14027, 2009.
[42]
K. E. Wellen and G. S. Hotamisligil, “Inflammation, stress, and diabetes,” Journal of Clinical Investigation, vol. 115, no. 5, pp. 1111–1119, 2005.
[43]
G. S. Hotamisligil, “Inflammation and metabolic disorders,” Nature, vol. 444, no. 7121, pp. 860–867, 2006.
[44]
T. Suganami, J. Nishida, and Y. Ogawa, “A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor α,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 10, pp. 2062–2068, 2005.
[45]
V. A. Fonseca, “Defining and characterizing the progression of type 2 diabetes,” Diabetes Care, vol. 32, supplement 2, pp. S151–S156, 2009.
[46]
S. C. Hanley, E. Austin, B. Assouline-Thomas et al., “β-cell mass dynamics and islet cell plasticity in human type 2 diabetes,” Endocrinology, vol. 151, no. 4, pp. 1462–1472, 2010.
[47]
E. H. Hathout, W. Thomas, M. El-Shahawy, F. Nahab, and J. W. Mace, “Diabetic autoimmune markers in children and adolescents with type 2 diabetes,” Pediatrics, vol. 107, no. 6, p. E102, 2001.
[48]
L. K. Gilliam, B. M. Brooks-Worrell, J. P. Palmer, C. J. Greenbaum, and C. Pihoker, “Autoimmunity and clinical course in children with type 1, type 2, and type 1.5 diabetes,” Journal of Autoimmunity, vol. 25, no. 3, pp. 244–250, 2005.
[49]
G. J. Klingensmith, L. Pyle, S. Arslanian et al., “The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study,” Diabetes Care, vol. 33, no. 9, pp. 1970–1975, 2010.
[50]
S. Than, H. Ishida, M. Inaba et al., “Bone marrow transplantation as a strategy for treatment of non-insulin- dependent diabetes mellitus in KK-Ay mice,” Journal of Experimental Medicine, vol. 176, no. 4, pp. 1233–1238, 1992.
[51]
N. G. Abraham, M. Li, L. Vanella, S. J. Peterson, S. Ikehara, and D. Asprinio, “Bone marrow stem cell transplant into intra-bone cavity prevents type 2 diabetes: role of heme oxygenase-adiponectin,” Journal of Autoimmunity, vol. 30, no. 3, pp. 128–135, 2008.
[52]
I. Boumaza, S. Srinivasan, W. T. Witt et al., “Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia,” Journal of Autoimmunity, vol. 32, no. 1, pp. 33–42, 2009.
[53]
E. J. Estrada, F. Valacchi, E. Nicora et al., “Combined treatment of intrapancreatic autologous bone marrow stem cells and hyperbaric oxygen in type 2 diabetes mellitus,” Cell Transplantation, vol. 17, no. 12, pp. 1295–1304, 2008.
[54]
S. C. Chua Jr., W. K. Chung, X. S. Wu-Peng et al., “Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor,” Science, vol. 271, no. 5251, pp. 994–996, 1996.
[55]
G. Fantuzzi and R. Faggioni, “Leptin in the regulation of immunity, inflammation, and hematopoiesis,” Journal of Leukocyte Biology, vol. 68, no. 4, pp. 437–446, 2000.
[56]
G. Matarese, S. Moschos, and C. S. Mantzoros, “Leptin in immunology,” Journal of Immunology, vol. 174, no. 6, pp. 3137–3142, 2005.
[57]
G. Fernandes, B. S. Handwerger, E. J. Yunis, and D. M. Brown, “Immune response in the mutant diabetic C57BL/Ks-db+ mouse. Discrepancies between in vitro and in vivo immunological assays,” Journal of Clinical Investigation, vol. 61, no. 2, pp. 243–250, 1978.
[58]
M. Kimura, S. I. Tanaka, F. Isoda, K. I. Sekigawa, T. Yamakawa, and H. Sekihara, “T lymphopenia in obese diabetic (db/db) mice is non-selective and thymus independent,” Life Sciences, vol. 62, no. 14, pp. 1243–1250, 1998.
[59]
M. Li, N. G. Abraham, L. Vanella et al., “Successful modulation of type 2 diabetes in db/db mice with intra-bone marrow-bone marrow transplantation plus concurrent thymic transplantation,” Journal of Autoimmunity, vol. 35, no. 4, pp. 414–423, 2010.
[60]
M. Li, L. Vanella, Y. Zhang, et al., “Stem cell transplantation increases antioxidant effects in diabetic mice,” International Journal of Biological Sciences, vol. 8, pp. 1335–1344, 2012.
[61]
L. Wang, S. Zhao, H. Mao, et al., “Autologous bone marrow stem cell transplantation for the treatment of type 2 diabetes mellitus,” Chinese Medical Journal, vol. 124, pp. 3622–3628, 2011.
