Congenic Mesenchymal Stem Cell Therapy Reverses Hyperglycemia in Experimental Type 1 Diabetes

Abstract

OBJECTIVEA number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well as determine the immunomodulatory effects of NOR MSCs in vivo.RESEARCH DESIGN AND METHODSNOR MSCs were evaluated with regard to their in vitro immunomodulatory function in the context of autoreactive T-cell proliferation and dendritic cell (DC) generation. The in vivo effect of NOR MSC therapy on reversal of recent-onset hyperglycemia and on immunogenic cell subsets in NOD mice was also examined.RESULTSNOR MSCs were shown to suppress diabetogenic T-cell proliferation via PD-L1 and to suppress generation of myeloid/inflammatory DCs predominantly through an IL-6-dependent mechanism. NOR MSC treatment of experimental type 1 diabetes resulted in long-term reversal of hyperglycemia, and therapy was shown to alter diabetogenic cytokine profile, to diminish T-cell effector frequency in the pancreatic lymph nodes, to alter antigen-presenting cell frequencies, and to augment the frequency of the plasmacytoid subset of DCs.CONCLUSIONSThese studies demonstrate the inimitable benefit of congenic MSC therapy in reversing experimental type 1 diabetes. These data should benefit future clinical trials using MSCs as treatment for type 1 diabetes.

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

“…In co-culture experiments, conditioned DCs induced a higher frequency of T cells with a regulatory phenotype and increased T cell secretion of anti-inflammatory IL-10 and TGF-β and IL-6 molecules. Therefore, an amplifying loop that mediates and propagates immunomodulation while inhibiting the maturation of inflammatory DCs can be envisaged [19]. Although data regarding the effects on beta cell function and survival remain controversial [45,46], IL-6 may also stimulate beta cell repair.…”

“…In NOD mice, MSC-released IL-6 has been reported to affect DC phenotype, differentiation and cytokine production and to divert the CD11c + subset toward a more regulatory tolerogenic phenotype [19]. Studies on the co-transplantation of allogenic islets and MSCs in streptozotocin-induced diabetic mice have shown that downregulation of the maturation, co-stimulatory and MHC class II molecules of recipient DCs contributes to graft survival by conversion to a more tolerogenic phenotype [20].…”

Preserved β-Cell Function in Type 1 Diabetes by Mesenchymal Stromal Cells

“…MSCs can be expanded ex vivo and have in a number of studies in animal models of type 1 diabetes been forwarded as an attractive therapy to ameliorate or reverse manifest diabetes (15)(16)(17). Besides having systemic immunomodulatory properties, the MSCs have been observed to specifically home to the damaged islets and to local pancreatic lymph nodes.…”

Two Distinct Mechanisms Mediate the Involvement of Bone Marrow Cells in Islet Remodeling: Neogenesis of Insulin-Producing Cells and Support of Islet Recovery

“…On the other hand, most studies have shown beneficial effects of cellular and cytokine interventions on islet remodeling and recovery from injury without significant conversion to produce insulin (8,12,19,33,39,40,42,45,66,68).…”

“…The first mechanism involves direct and indirect support of revascularization and neovascularization, which has been demonstrated for whole bone marrow cells (BMCs) (8,19,39,64), adherent BMC subsets (39,40,45), lineagenegative (lin − ) (19,47), and c-kit + lin − progenitors (19). The second mechanism involves local immunomodulation attained by MSCs (7,33,40,42), and one or multiple BMC infusions (6,19). Combined vascular and immunogenic activities have been also achieved by bone marrow activation with 5-fluorouracil (8), mobilization (64), and cotransplantation (43).…”