Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells

Abstract

BackgroundInability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet β cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D.MethodsWe developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n = 15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41), and median diabetic history was 8 years (range: 1 to 21).ResultsStem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual β cell function (n = 6) and patients with no residual pancreatic islet β cell function (n = 6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n = 3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance.ConclusionsStem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet β cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches.Trial registrationClinicalTrials.gov number, NCT01350219.

Role of regeneration in tissue repairing and therapies

“…Stem cells also help in dental cares by inducing regeneration or differentiation of dental epithelia into enamel-producing ameloblasts [86]. MSCs implanted in pancreas can replace defective islet beta cells, enhance β-cell proliferation [87], cure type 1 diabetes [88] and do its reversal [89,90,98,99] in non-obese diabetic mice [91,92]. Similarly, implantation of multipotent stem cells implanted in bone marrow can suppress ovarian cancer and stop metastasis [90,92].…”

“…MSCs implanted in pancreas can replace defective islet beta cells, enhance β-cell proliferation [87], cure type 1 diabetes [88] and do its reversal [89,90,98,99] in non-obese diabetic mice [91,92]. Similarly, implantation of multipotent stem cells implanted in bone marrow can suppress ovarian cancer and stop metastasis [90,92]. These are also implanted to remove incurable defects like tumors by counterbalance between mature BDNF and proBDNF factors that may regulate tumor growth [88,93].…”

Cell Replacement Strategies Aimed at Reconstitution of the β-Cell Compartment in Type 1 Diabetes

“…Thus, they have been successfully tested for their ability to reset the immunological clock of diabetes (88,89). Cord blood2derived multipotent stem cells (CB-SCs) are also the basis of the novel "stem cell educator" concept, in which lymphocytes of type 1 diabetic patients are circulated through a device preseeded with CBSCs from healthy donors and reinfused into the patient after a quick process of "re-education" that has been reported to reverse type 1 diabetes (90,91). These findings, however, still require independent confirmation.…”

Factors determining insulin requirements in women with type 1 diabetes mellitus during pregnancy: a review

“…104 Alternatively, these mesenchymal stem cells may re-educate maternal lymphocytes. Zhao et al 105 used a ''stem cell educator'' which comprised a closed loop system that co-cultured lymphocytes from T1DM patients with cord-blood stem cells in vitro.…”