Successful modulation of type 2 diabetes in db/db mice with intra-bone marrow–bone marrow transplantation plus concurrent thymic transplantation
Introduction
There is a virtual epidemic of type 2 diabetes, and although the mechanisms for this increase are not entirely clear, it has become the focus of both genetic and environmental research [1]. Clearly, inflammation has a critical role in the development of metabolic diseases, including obesity and T2 DM [1]. Recently, it has been shown that obese adipose tissue activates CD8T cells, resulting in promoting the recruitment and activation of macrophages in the adipose tissue [2]; macrophages have been shown to infiltrate the adipose tissue in mice and humans [3]. Adipocytes regulate and mediate inflammatory cytokines such as tumor necrosis factor-α (TNFα), IL-6, matrixmetalloproteinases (MMPs), peroxisome proliferation activated receptor-r (PPAR-r) and fatty acid-binding protein –4. These cytokines inhibit or enhance each other, and their activities contribute to insulin resistance [4]. As such, both an autoinflammatory as well as an autoimmune response are involved in the pathogenesis of T2 DM.
Bone marrow transplantation (BMT) has been demonstrated to treat hematopoietic disorders, metabolic disorders and autoimmune diseases [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. We have recently found that intra-bone marrow–BMT (IBM–BMT) treatment is an advantageous strategy for allogeneic BMT, compared with conventional intravenous BMT [23], since IBM–BMT can replace not only hemopoietic cells (including hemopoietic stem cells:HSCs) but also stromal cells (including mesenchymal stem cells:MSCs). In addition, we have very recently found that thymus transplantation combined with BMT (BMT + TT) is a powerful strategy to ameliorate thymic involution in recipient mice due to aging or irradiation [20], [21], [22].
Based on these findings, we carried out IBM–BMT in combination with newborn thymus transplantation (TT) in db/db mice. We here demonstrate that, after IBM–BMT + TT treatment in db/db mice, insulin sensitivity increases and blood glucose levels decrease, resulting from the normalization of balance of lymphocyte subsets and cytokines, followed by enhanced expression of pAKT, pLKB1, pAMPK, insulin receptor phosphorylation and HO-1. This suggests that the maintenance of the balance of lymphocyte subsets and cytokine production by IBM–BMT + TT treatment is essential for the amelioration of T2 DM in db/db mice.
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Animals
Five-week-old BKS.Cg-m+Leprdb/+Leprdb/J (H-2kd) (db/db) mice, BKS. Cg-m+/+Leprdb/J(H-2kd) (lean) mice and C57BL/6 (B6) (H-2kb) mice were purchased from Charles River Laboratories (Yokohama, Japan) and SLC (Shizuoka, Japan) and maintained in animal facilities under specific pathogen-free conditions. All procedures were performed under protocols approved by the Institutional Animal Care and Use Committee at Kansai Medical University. Body weight and blood glucose levels were measured each week.
Body weight, blood glucose levels, insulin sensitivity, and plasma adiponectin, insulin, IL-6 and IL-1β levels
In our preliminary experiments, we carried out IBM–BMT alone (without TT). The IBM–BMT-treated db/db mice showed decreased blood glucose levels (<150 mg/ml) one week after the treatment but rapid increases in blood glucose levels 2 weeks after the treatment; the mice became susceptible to severe infection due to a rebound phenomenon, and died. Therefore, in the present study, we carried out IBM–BMT + TT, and non-treated db/db mice were used as the control.
As seen in Fig. 1A, a gain in body
Discussion
Leptin is an adipocyte-derived hormone that links nutritional status with neuroendocrine and immune functions. Leptin has been shown to modulate T cell proliferation, to promote Th1 responses, and to protect thymocytes from corticosteroid-induced apoptosis in vitro [26], [27], [28], [29]. Leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice exhibit severe hereditary obesity [30], [31] and display hormonal imbalances and hematolymphoid defects [32], [33]. Db/db mice exhibit a
Acknowledgments
We would like to thank Mr. Hilary Eastwick-Field and Ms. K. Ando for their help in the preparation of the manuscript. This study was mainly supported by the 21st Century Center of Excellence (COE) program of the Ministry of Education, Culture, Sports, Science and Technology. This study was also supported by grants from Haiteku Research Center of the Ministry of Education, Health and Labour Sciences Research Grants, the Science Frontier program of the Ministry of Education, Culture, Sports,
References (58)
Bone marrow transplantation, refractory autoimmunity and the contributions of Susumu Ikehara
J Autoimmun
(2008)A novel method of bone marrow transplantation (BMT) for intractable autoimmune diseases
J Autoimmun
(2008)- et al.
Hematopoietic stem cell transplantation for autoimmune diseases: what have we learned?
J Autoimmun
(2008) - et al.
Cell and gene therapy using mesenchymal stem cells (MSCs)
J Autoimmun
(2008) - et al.
Bone marrow stem cell transplant into intra-bone cavity prevents type 2 diabetes: role of heme oxygenase-adiponectin
J Autoimmun
(2008) Immunophenotype and functional characteristics of human primitive CD34-negative hematopoietic stem cells: the significance of the intra-bone marrow injection
J Autoimmun
(2008)Will hematopoietic stem cell transplantation cure human autoimmune diseases?
J Autoimmun
(2008)- et al.
Hunt for pluripotent stem cell – regenerative medicine search for almighty cell
J Autoimmun
(2008) - et al.
In vivo bioimaging using photogenic rats: fate of injected bone marrow-derived mesenchymal stromal cells
J Autoimmun
(2008) - et al.
Separation of graft-vs.-tumor effects from graft-vs.-host disease in allogeneic hematopoietic cell transplantation
J Autoimmun
(2008)