The Antidiabetic Effect of MSCs Is Not Impaired by Insulin Prophylaxis and Is Not Improved by a Second Dose of Cells

Abstract

Type 1 diabetes mellitus (T1D) is due to autoimmune destruction of pancreatic beta-cells. Previously, we have shown that intravenously administered bone marrow-derived multipotent mesenchymal stromal cells (MSCs) allows pancreatic islet recovery, improves insulin secretion and reverts hyperglycemia in low doses streptozotocin (STZ)-induced diabetic mice. Here we evaluate whether insulin prophylaxis and the administration of a second dose of cells affect the antidiabetic therapeutic effect of MSC transplantation. Insulitis and subsequent elimination of pancreatic beta-cells was promoted in C57BL/6 mice by the injection of 40 mg/kg/day STZ for five days. Twenty-four days later, diabetic mice were distributed into experimental groups according to if they received or not insulin and/or one or two doses of healthy donor-derived MSCs. Three and half months later: glycemia, pancreatic islets number, insulinemia, glycated hemoglobin level and glucose tolerance were determined in animals that did not received exogenous insulin for the last 1.5 months. Also, we characterized MSCs isolated from mice healthy or diabetic. The therapeutic effect of MSC transplantation was observed in diabetic mice that received or not insulin prophylaxis. Improvements were similar irrespective if they received one or two doses of cells. Compared to MSCs from healthy mice, MSCs from diabetic mice had the same proliferation and adipogenic potentials, but were less abundant, with altered immunophenotype and no osteogenic potential.Our preclinical results should be taken into account when designing phase II clinical trials aimed to evaluate MSC transplantation in patients with T1D. Cells should be isolated form healthy donor, insulin prophylaxis could be maintained and a second dose, after an elapse of two months, appears unnecessary in the medium-term.

Effect of Bone Marrow Versus Adipose Tissue Derived Mesenchymal Stem Cells on the Pancreas of Streptozotocin-Induced Diabetes Mellitus Type I in Adult Male Rats (Histological Study)

“…The H& E stained sections revealed apparently normal histological structure of the islets of Langerhans and pancreatic acini with minimal affection in the treated groups (III &IV). These findings are similar to what was detected in previous studies [3,34] where BMSCs transplantation group had nearly normal islets of Langerhans. In addition further support could be attained by a former study [14] which reported that intravenous injection of AMSCs decreased the islets cells degeneration induced by STZ, lowered the fasting blood glucose and increased insulin secretion by β -cells when compared to the diabetic group.…”

“…Type I diabetes represents 10% of the diabetic cases with increased incidence in the developed countries [3] . It is an autoimmune destruction of the pancreatic insulin producing β-cells that resulted from abnormal activation of T-cells [4] .…”

Infusion with Human Bone Marrow-derived Mesenchymal Stem Cells Improves β-cell Function in Patients and Non-obese Mice with Severe Diabetes

“…While infusion with a single-dose of MSCs induces transiently decreases in blood glucose in diabetic mice1920 infusion with multiple-dose of MSCs can effectively restore glucose homeostasis by inhibiting oxidative stress and promoting functional β-cell repair in STZ-induced Balb/c and NOD/scid mice15162122. To optimize the therapeutic effect of MSC infusion on severe diabetes, we compared the effects of infusion with different doses of MSCs in NOD mice with severe T1D.…”

“…In addition, therapeutic effects of MSC transplantation are associated with modulation of autoimmunity456, however, the mechanisms underlying the action of infused MSCs in a severe diabetic condition have not been clarified. Moreover, whether the therapeutic effects of MSC transplantation is dose-dependent and whether repeated infusion is necessary for preserving β-cell function are still in debate1516.…”

Bone Marrow Stem Cell as a Potential Treatment for Diabetes

“…The transplantation of insulin-producing cells from adult hBMSCs into nude diabetic mice resulted in the control of their diabetic status for 3 months [27]. Recent reports have demonstrated that human bone marrow MSCs (hBMMSCs) improved blood glucose control and ameliorated diabetes in animal models [28–31]. One report has described the possible benefit of hBMMSCs for the treatment of insulin-dependent diabetes and gives new insight into the mechanism of β -cell recovery after injury mediated by hBMMSC therapy [32].…”