Purpose: Major barriers to effective adenovirus-based gene therapy include induction of an immune response and tumor-specific targeting of vectors. The use of mesenchymal stem cells (MSC) as systemic delivery vehicles for therapeutic genes has been proposed as a result of their combined ability to home in on the tumor site and evade the host immune response. This study is aimed at investigating factors mediating homing of human MSCs to breast cancer primary cultures and cell lines in vitro and in vivo.

Background Bone-marrow derived mesenchymal stem cells (MSCs) reduce the severity of evolving acute lung injury (ALI), but their ability to repair the injured lung is not clear. A study was undertaken to determine the potential for MSCs to enhance repair after ventilator-induced lung injury (VILI) and elucidate the mechanisms underlying these effects. Methods Anaesthetised rats underwent injurious ventilation which produced severe ALI. Following recovery, they were given an intravenous injection of MSCs (2×10⁶ cells) or vehicle immediately and a second dose 24 h later. The extent of recovery following VILI was assessed after 48 h. Subsequent experiments examined the potential for non-stem cells and for the MSC secretome to enhance VILI repair. The contribution of specific MSC-secreted mediators was then examined in a wound healing model. Results MSC therapy enhanced repair following VILI. MSCs enhanced restoration of systemic oxygenation and lung compliance, reduced total lung water, decreased lung inflammation and histological lung injury and restored lung structure. They attenuated alveolar tumour necrosis factor α concentrations while increasing concentrations of interleukin 10. These effects were not seen with non-stem cells (ie, rat fibroblasts). MSC-secreted products also enhanced lung repair and attenuated the inflammatory response following VILI. The beneficial effect of the MSC secretome on repair of pulmonary epithelial wounds was attenuated by prior depletion of keratinocyte growth factor. Conclusion MSC therapy enhances lung repair following VILI via a paracrine mechanism that may be keratinocyte growth factor-dependent.

Background: Omental fat accumulation is associated with development of the metabolic syndrome, although its molecular characteristics are poorly understood. Mi(cro)RNAs (miRNAs), a class of small noncoding RNAs, are known to regulate various metabolic processes, although their role in obesity and the metabolic syndrome is not clearly defined. This study sought to characterize the miRNA expression in omentum, sc fat and in the circulation of obese and nonobese individuals. Their potential as noninvasive metabolic biomarkers was also explored. Methods: miRNA was extracted from paired omentum and sc fat tissues, and blood samples, from a total of 50 obese and nonobese patients. A miRNA microarray was performed and a panel of differentially expressed miRNAs validated using RQ-PCR. Results: The miRNA expression profiles were unique for omentum and paired sc fat; no correlation in miRNA expression was observed between these two fat depots. Expression of two miRNAs (miR-17–5p and miR-132) differed significantly between obese and nonobese omental fat (P = 0.048 and P = 0.016). This expression pattern was reflected in the circulation in which these same two miRNAs were also significantly dysregulated in blood from obese subjects. The miRNA expression in omental fat and blood from obese patients correlated significantly with body mass index, fasting blood glucose, and glycosylated hemoglobin. Conclusion: This study demonstrates that candidate metabolic miRNAs are altered in adipose tissue and circulation of the obese. Omental fat tissue and systemic miRNA levels reflect components of the metabolic syndrome, highlighting their potential as novel biomarkers for this complex syndrome.

Mesenchymal stromal cells (MSCs) demonstrate considerable promise in preclinical acute respiratory distress syndrome models. We wished to determine the efficacy and mechanisms of action of human MSCs (hMSCs) in the setting of acute lung injury induced by prolonged Escherichia coli pneumonia in the rat. Adult male Sprague Dawley rats underwent intratracheal instillation of E. coli bacteria in all experiments. In Series 1, animals were randomised to intravenous administration of: (1) vehicle (phosphate buffered saline (PBS), 300 μL); (2) 1×10(7) fibroblasts/kg; (3) 1×10(7) hMSCs/kg or (4) 2×10(7) hMSCs/kg. Series 2 determined the lowest effective hMSC dose. Series 3 compared the efficacy of intratracheal versus intravenous hMSC administration, while Series 4 examined the efficacy of cryopreserved hMSC. Series 5 examined the efficacy of the hMSC secretome. Parallel in vitro experiments further assessed the potential for hMSCs to secrete LL-37 and modulate macrophage phagocytosis. hMSC therapy reduced the severity of rodent E. coli pneumonia, improving survival, decreasing lung injury, reducing lung bacterial load and suppressing inflammation. Doses as low as 5×10(6) hMSCs/kg were effective. Intratracheal hMSC therapy was as effective as intravenous hMSC. Cryopreserved hMSCs were also effective, while the hMSC secretome was less effective in this model. hMSC therapy enhanced macrophage phagocytic capacity and increased lung and systemic concentrations of the antimicrobial peptide LL37. hMSC therapy decreased E. coli induced pneumonia injury and reduced lung bacterial burden, potentially via enhanced macrophage phagocytosis and increased alveolar LL-37 concentrations.