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

Abstract

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease that results from cell-mediated autoimmune destruction of insulin-producing cells. In T1DM animal models, it has been shown that the systemic administration of multipotent mesenchymal stromal cells, also referred as to mesenchymal stem cells (MSCs), results in the regeneration of pancreatic islets. Mechanisms underlying this effect are still poorly understood. Our aims were to assess whether donor MSCs (a) differentiate into pancreatic b-cells and (b) modify systemic and pancreatic pathophysiologic markers of T1DM. After the intravenous administration of 5 3 10 5 syngeneic MSCs, we observed that mice with T1DM reverted their hyperglycemia and presented no donor-derived insulin-producing cells. In contrast, 7 and 65 days post-transplantation, MSCs were engrafted into secondary lymphoid organs. This correlated with a systemic and local reduction in the abundance of autoaggressive T cells together with an increase in regulatory T cells. Additionally, in the pancreas of mice with T1DM treated with MSCs, we observed a cytokine profile shift from proinflammatory to antinflammatory. MSC transplantation did not reduce pancreatic cell apoptosis but recovered local expression and increased the circulating levels of epidermal growth factor, a pancreatic trophic factor. Therefore, the antidiabetic effect of MSCs intravenously administered is unrelated to their transdifferentiation potential but to their capability to restore the balance between Th1 and Th2 immunological responses along with the modification of the pancreatic microenvironment. Our data should be taken into account when designing clinical trials aimed to evaluate MSC transplantation in patients with T1DM since the presence of endogenous precursors seems to be critical in order to restore glycemic control.

Alterations in the Cellular Immune Compartment of Patients Treated with Third-Party Mesenchymal Stromal Cells Following Allogeneic Hematopoietic Stem Cell Transplantation

“…3F) indicating an MSC-associated skewing toward T H 2 responses, which is in line with previous observations [12]. Pro-inflammatory cytokines TNF-a and IL-1a did not differ significantly between both groups (Fig.…”

“…Acute GVHD is considered to be a T H 1-driven disease [1]. MSCs re-establish the balance between T H 1 and T H 2 responses in models of autoimmunity [12] and GVHD [26]. We evaluated IFN-c and IL-4 as prototypic T H 1 and T H 2 cytokines, respectively, and observed a significant skewing toward a T H 2 response in the MSC group (Fig.…”

Mesenchymal Stromal Cells to Halt the Progression of Type 1 Diabetes?

“…Also in MLDS-treated C57BL/6 mice, MSCs have improved metabolic control and even reversed the hyperglycemia [89]. This effect was later ascribed unrelated to the transdifferentiation potential of the cells, but to their capability to restore the Th1/Th2 balance and to modify the pancreatic microenvironment [90]. Streptozotocin-treated rats injected with MSCs have similarly been shown to become normoglycemic, and MSCs in the islet microenvironment were shown to cause higher frequencies of CD4-and CD8-positive FOXp3 T cells with a shift toward interleukin-10 and interleukin-13 production [91].…”

“…In co-culture experiments of MSCs and peripheral blood mononuclear cells Multiple low-dose streptozotocin-treated C57BL/6 mice Reversed diabetes -MSCs engrafted into secondary lymph nodes -Shift from Th1 to Th2 immunological response -Increased expression of epidermal growth factor in the pancreas [89,90] Streptozotocin-treated rats Reversed diabetes -Homing of MSCs to the pancreas and islets -Higher frequencies of regulatory T cells. Shifted T cells to interleukin-10 and interleukin-13 production [91] NOD mice Reversed diabetes -Homing to the pancreatic lymph nodes -Shift towards a Th2 like immune response [92] NOD mice Reversed diabetes -Diminished T cell effector frequency in the pancreatic lymph nodes -Changed the systemic cytokine profile -Altered the antigen-presenting cell frequencies -Augmented the plasmacytoid subset of dendritic cells [93] NOD mice Reversed diabetes -Shift toward a Th2-like immune response -Expansion of regulatory T cells in the pancreatic lymph nodes -Reduced inflammatory cell and interferon-γ levels in the pancreas [94] NOD mice Prevented diabetes development -Homing to the pancreatic lymph nodes -Induction of regulatory T cells [95] NOD mice Prevented diabetes development -Inhibited activation of T cells and enhanced the frequencies of regulatory T cells by tumor necrosis factor-α stimulated gene/protein 6 [72•] (PBMCs) from type 1 diabetes patients, the MSCs abrogated a proinflammatory Th1 response following GAD stimulation, and decreased the PBMC secretion of interferon-γ and interleukin-10, while increasing the interleukin-4 secretion [96].…”

Immunogenicity of allogeneic mesenchymal stem cells transplanted via different routes in diabetic rats

“…These results suggest that MSCs may shift the balance of T-cell subsets from pro-inflammatory to anti-inflammatory, as described previously. 28 According to Liu et al, 29 these immunomodulatory effects may be due to MSC secretion of various cytokines, especially KGF, to modulate the thymic microenvironment. These immunological changes may contribute to the reduction of inflammatory injury of b cells and restored BG homeostasis, although other mechanisms may be involved in the process, such as the secretion of bioactive factors (IL-6, HGF, TGF-b1, SDF-1, VEGF, IL-1b, PGE) and reduction of systemic oxidative stress.…”