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To explore the long-term safety and benefit of umbilical cord mesenchymal stromal cell (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). In the primary completion of this trial (ClinicalTrials.gov identifier: NCT01374854), the authors randomized patients (n = 21 per group) to either SCT or standard care (control) and previously reported effects on insulin secretion. The authors report about the incidence of chronic diabetes complications (primary endpoint) after 8 years of follow-up. The authors also report on secondary endpoints, safety, islet function and metabolic control. Data were obtained from 14 of 21 patients in the SCT group and 15 of 21 patients in the control group who completed follow-up. At 8 years, the incidence of peripheral neuropathy was 7.1% (one of 14) in the SCT group versus 46.7% (seven of 15) in the control group (P = 0.017). The incidence of diabetic nephropathy was 7.1% (one of 14) in the SCT group versus 40.0% (six of 15) in the control group (P = 0.039). The incidence of retinopathy was 7.1% (one of 14) in the SCT group versus 33.3% (five of 15) in the control group (P = 0.081). Two patients (two of 14, 14.3%) in the SCT group and 11 patients (11 of 15, 73.3%) in the control group developed at least one complication (P = 0.001). One and six patients in the SCT group and control group, respectively, had at least two complications (P = 0.039). No malignancies were reported in the treated group. Co-transplantation of umbilical cord MSCs and aBM-MNCs in patients with established T1D was associated with reduced incidence of chronic diabetes complications. [ABSTRACT FROM AUTHOR]

Background: Hypoxia is a major cause of beta cell death and dysfunction after transplantation. The aim of this study was to investigate the effect of exosomes derived from mesenchymal stem cells (MSCs) on beta cells under hypoxic conditions and the potential underlying mechanisms. Methods: Exosomes were isolated from the conditioned medium of human umbilical cord MSCs and identified by WB, NTA, and transmission electron microscopy. Beta cells (βTC-6) were cultured in serum-free medium in the presence or absence of exosomes under 2% oxygen conditions. Cell viability and apoptosis were analysed with a CCK-8 assay and a flow cytometry-based annexin V-FITC/PI apoptosis detection kit, respectively. Endoplasmic reticulum stress (ER stress) proteins and apoptosis-related proteins were detected by the WB method. MiRNAs contained in MSC exosomes were determined by Illumina HiSeq, and treatment with specific miRNA mimics or inhibitors of the most abundant miRNAs was used to reveal the underlying mechanism of exosomes. Results: Exosomes derived from MSC-conditioned culture medium were 40–100 nm in diameter and expressed the exosome markers CD9, CD63, CD81, HSP70, and Flotillin 1, as well as the MSC markers CD73, CD90, and CD105. Hypoxia significantly induced beta cell apoptosis, while MSC exosomes remarkably improved beta cell survival. The WB results showed that ER stress-related proteins, including GRP78, GRP94, p-eIF2α and CHOP, and the apoptosis-related proteins cleaved caspase 3 and PARP, were upregulated under hypoxic conditions but were inhibited by MSC exosomes. Moreover, the p38 MAPK signalling pathway was activated by hypoxia and was inhibited by MSC exosomes. The Illumina HiSeq results show that MSC exosomes were rich in miR-21, let-7 g, miR-1246, miR-381, and miR-100. After transfection with miRNA mimics, the viability of beta cells under hypoxia was increased significantly by miR-21 mimic, and the p38 MAPK and ER stress-related proteins in beta cells were downregulated. These changes were reversed after exosomes were pretreated with miR-21 inhibitor. Conclusions: Exosomes derived from MSCs could protect beta cells against apoptosis induced by hypoxia, largely by carrying miR-21, alleviating ER stress and inhibiting p38 MAPK signalling. This result indicated that MSC exosomes might improve encapsulated islet survival and benefit diabetes patients. [ABSTRACT FROM AUTHOR]

Objective: To determine the safety and effects on insulin secretion of umbilical cord (UC) mesenchymal stromal cells (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D).Research Design and Methods: Between January 2009 and December 2010, 42 patients with T1D were randomized (n = 21/group) to either SCT (1.1 × 10(6)/kg UC-MSC, 106.8 × 10(6)/kg aBM-MNC through supraselective pancreatic artery cannulation) or standard care (control). Patients were followed for 1 year at 3-month intervals. The primary end point was C-peptide area under the curve (AUC(C-Pep)) during an oral glucose tolerance test at 1 year. Additional end points were safety and tolerability of the procedure, metabolic control, and quality of life.Results: The treatment was well tolerated. At 1 year, metabolic measures improved in treated patients: AUCC-Pep increased 105.7% (6.6 ± 6.1 to 13.6 ± 8.1 pmol/mL/180 min, P = 0.00012) in 20 of 21 responders, whereas it decreased 7.7% in control subjects (8.4 ± 6.8 to 7.7 ± 4.5 pmol/mL/180 min, P = 0.013 vs. SCT); insulin area under the curve increased 49.3% (1,477.8 ± 1,012.8 to 2,205.5 ± 1,194.0 mmol/mL/180 min, P = 0.01), whereas it decreased 5.7% in control subjects (1,517.7 ± 630.2 to 1,431.7 ± 441.6 mmol/mL/180 min, P = 0.027 vs. SCT). HbA1c decreased 12.6% (8.6 ± 0.81% [70.0 ± 7.1 mmol/mol] to 7.5 ± 1.0% [58.0 ± 8.6 mmol/mol], P < 0.01) in the treated group, whereas it increased 1.2% in the control group (8.7 ± 0.9% [72.0 ± 7.5 mmol/mol] to 8.8 ± 0.9% [73 ± 7.5 mmol/mol], P < 0.01 vs. SCT). Fasting glycemia decreased 24.4% (200.0 ± 51.1 to 151.2 ± 22.1 mg/dL, P < 0.002) and 4.3% in control subjects (192.4 ± 35.3 to 184.2 ± 34.3 mg/dL, P < 0.042). Daily insulin requirements decreased 29.2% in only the treated group (0.9 ± 0.2 to 0.6 ± 0.2 IU/day/kg, P = 0.001), with no change found in control subjects (0.9 ± 0.2 to 0.9 ± 0.2 IU/day/kg, P < 0.01 vs. SCT).Conclusions: Transplantation of UC-MSC and aBM-MNC was safe and associated with moderate improvement of metabolic measures in patients with established T1D. [ABSTRACT FROM AUTHOR]

Background: Renal ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal allograft. This study aimed at investigating the effects ofmesenchymal stem cells (MSC) on ischemia/reperfusion (I/R) injury and the underlying mechanisms in a rat model. Methods: Renal ischemia was produced by clamping the right renal vessels for 60 min after the left kidney was removed. Immediately after visual confirmation of reflow, 1 × 106 MSC were administered by intravenous injection, followed by reperfusion for 24 h. The kidney functions, tissue malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels were evaluated. Histopathological examinations were also performed. Results: MSC infusion significantly improved kidney function as indicated by lower urea and creatinine levels in the MSC compared to the vehicle group (p < 0.05). I/R-induced reduction in renal tissue SOD enzyme activity and GSH-Px was significantly improved by MSC (p < 0.05). Treatment with MSC also resulted in significant reduction in renal tissue MDA levels that were increased by renal I/R injury (p < 0.05). At histological examination, the kidneys of MSC-treated rats showed a fairly normal morphology. Conclusions: MSC protects the kidneys against I/R injury at least via their antioxidant effects. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]