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Background: Adipose tissue-derived mesenchymal stem cells (AT-MSCs) offer potential as a therapeutic option for chronic discogenic low back pain (LBP) because of their immunomodulatory functions and capacity for cartilage differentiation. The goal of this study was to assess the safety and tolerability of a single intradiscal implantation of combined AT-MSCs and hyaluronic acid (HA) derivative in patients with chronic discogenic LBP. Methods: We performed a single-arm phase I clinical trial with a 12-month follow-up and enrolled 10 eligible chronic LBP patients. Chronic LBP had lasted for more than 3 months with a minimum intensity of 4/10 on a visual analogue scale (VAS) and disability level ≥ 30% on the Oswestry Disability Index (ODI). The 10 patients underwent a single intradiscal injection of combined HA derivative and AT-MSCs at a dose of 2 × 107 cells/disc (n=5) or 4×107 cells/disc (n=5). Safety and treatment outcomes were evaluated by assessing VAS, ODI, Short Form-36 (SF-36), and imaging (lumbar spine X-ray imaging and MRI) at regular intervals over 1 year. Results: No patients were lost at any point during the 1-year clinical study. We observed no procedure or stem cell-related adverse events or serious adverse events during the 1-year follow-up period. VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses, and did not differ significantly between the two groups. Among six patients who achieved significant improvement in VAS, ODI, and SF-36, three patients (cases 4, 8, and 9) were determined to have increased water content based on an increased apparent diffusion coefficient on diffusion MRI. Conclusions: Combined implantation of AT-MSCs and HA derivative in chronic discogenic LBP is safe and tolerable. However, the efficacy of combined AT-MSCs and HA should be investigated in a randomized controlled trial in a larger population. [ABSTRACT FROM AUTHOR]

Introduction: Despite the success of interventional processes such as drug-eluting stents, complete prevention of restenosis is still hindered by impaired or delayed endothelialization or both. Here, we report that 1H-pyrrole-2,5-dione-based small molecule-generated mesenchymal stem cell-derived functional endothelial cells (MDFECs) facilitated rapid transmural coverage of injured blood vessels. Methods: Small molecules that induced CD31 expression were screened by principal component analysis (PCA). Rat mesenchymal stem cells (MSCs) were treated with selected small molecules for up to 16 days, and the expression levels of CD90 and CD31 were examined by immunocytochemistry. In vitro functional assays of MDFECs, including tube formation assays and nitric oxide production assays, were performed. After MDFECs (intravenous, 3×106 cells per animal) were injected into balloon-injured rats, neointima formation was monitored for up to 21 days. The endothelial coverage of denuded blood vessels was evaluated by Evans Blue staining. The functionality of repaired blood vessels was evaluated by measuring vasorelaxation and hemodynamic changes. Additionally, derivatives of the selected small molecules were examined for their ability to induce endothelial markers. Results: PCA indicated that 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione effectively induced MDFECs. MDFECs inhibited the neointima formation of denuded blood vessels by facilitating more rapid endothelialization. Further examination indicated that derivatives with a 1H-pyrrole-2,5-dione moiety are important for initiating the endothelial cell differentiation of MSCs. Conclusions: Small molecules with 1H-pyrrole-2,5-dione as a core structure have great potential to improve the efficacy of MSC-based cell therapy for vascular diseases, such as atherosclerosis and restenosis. [ABSTRACT FROM AUTHOR]

Introduction: Mesenchymal stem cells (MSCs) have therapeutic potential for the repair of myocardial injury. The efficacy of MSC therapy for myocardial regeneration mainly depends on the survival of cells after transplantation into the infarcted heart. In the transplanted regions, reactive oxygen species (ROS) can cause cell death, and this process depends on caspase activation and autophagosome formation. Methods: A Software TargetScan was utilized to search for microRNAs (miRNAs) that target caspase-3 mRNA. Six candidate miRNAs including let-7b were selected and transfected into human MSCs in vitro. Expression of MEK-EKR signal pathways and autophagy-related genes were detected. Using ischemia/reperfusion model (I/R), the effect of MSCs enriched with let-7b was determined after transplantation into infarcted heart area. Miller catheter was used to evaluate cardiac function. Results: Here, we report that let-7b targets caspase-3 to regulate apoptosis and autophagy in MSCs exposed to ROS. Let-7b-transfected MSCs (let-7b-MSCs) showed high expression of survival-related proteins, including p-MEK, p-ERK and Bcl-2, leading to a decrease in Annexin V/PI- and TUNEL-positive cells under ROS-rich conditions. Moreover, autophagy-related genes, including Atg5, Atg7, Atg12 and beclin-1, were significantly downregulated in let-7b-MSCs. Using a rat model of acute myocardial infarction, we found that intramyocardial injection of let-7b-MSCs markedly enhanced left ventricular (LV) function and microvessel density, in accordance with a reduced infarct size and the expression of caspase-3. Conclusions: Taken together, these data indicate that let-7b may protect MSCs implanted into infarcted myocardium from apoptosis and autophagy by directly targeting caspase-3 signaling. [ABSTRACT FROM AUTHOR]

Abstract Background Adipose tissue-derived mesenchymal stem cells (AT-MSCs) offer potential as a therapeutic option for chronic discogenic low back pain (LBP) because of their immunomodulatory functions and capacity for cartilage differentiation. The goal of this study was to assess the safety and tolerability of a single intradiscal implantation of combined AT-MSCs and hyaluronic acid (HA) derivative in patients with chronic discogenic LBP. Methods We performed a single-arm phase I clinical trial with a 12-month follow-up and enrolled 10 eligible chronic LBP patients. Chronic LBP had lasted for more than 3 months with a minimum intensity of 4/10 on a visual analogue scale (VAS) and disability level ≥ 30% on the Oswestry Disability Index (ODI). The 10 patients underwent a single intradiscal injection of combined HA derivative and AT-MSCs at a dose of 2 × 107 cells/disc (n = 5) or 4 × 107 cells/disc (n = 5). Safety and treatment outcomes were evaluated by assessing VAS, ODI, Short Form-36 (SF-36), and imaging (lumbar spine X-ray imaging and MRI) at regular intervals over 1 year. Results No patients were lost at any point during the 1-year clinical study. We observed no procedure or stem cell-related adverse events or serious adverse events during the 1-year follow-up period. VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses, and did not differ significantly between the two groups. Among six patients who achieved significant improvement in VAS, ODI, and SF-36, three patients (cases 4, 8, and 9) were determined to have increased water content based on an increased apparent diffusion coefficient on diffusion MRI. Conclusions Combined implantation of AT-MSCs and HA derivative in chronic discogenic LBP is safe and tolerable. However, the efficacy of combined AT-MSCs and HA should be investigated in a randomized controlled trial in a larger population. Trial registration ClinicalTrials.gov NCT02338271 . Registered 7 January 2015.