The aim of this study was to investigate the effects of subconjunctivally administered mesenchymal stem cells (MSCs) on corneal wound healing in the acute stage of an alkali burn. A corneal alkali burn model was generated by placing a piece of 3-mm diameter filter paper soaked in NaOH on the right eye of 48 Sprague-Dawley female rats. 24 rats were administered a subconjunctival injection of a suspension of 2×106 MSCs in 0.1 ml phosphate-buffered saline (PBS) on day 0 and day 3 after the corneal alkali burn. The other 24 rats were administered a subconjunctival injection of an equal amount of PBS as a control. Deficiencies of the corneal epithelium and the area of corneal neovascularization (CNV) were evaluated on days 3 and 7 after the corneal alkali burn. Infiltrated CD68+ cells were detected by immunofluorescence staining. The mRNA expression levels of macrophage inflammatory protein-1 alpha (MIP-1α), tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) were analyzed using real-time polymerase chain reaction (real-time PCR). In addition, VEGF protein levels were analyzed using an enzyme-linked immunosorbent assay (ELISA). MSCs significantly enhanced the recovery of the corneal epithelium and decreased the CNV area compared with the control group. On day 7, the quantity of infiltrated CD68+ cells was significantly lower in the MSC group and the mRNA levels of MIP-1α, TNF-α, and VEGF and the protein levels of VEGF were also down-regulated. However, the expression of MCP-1 was not different between the two groups. Our results suggest that subconjunctival injection of MSCs significantly accelerates corneal wound healing, attenuates inflammation and reduces CNV in alkaline-burned corneas; these effects were found to be related to a reduction of infiltrated CD68+ cells and the down-regulation of MIP-1α, TNF-α and VEGF.

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We consider the problem of peak-to-average power ratio (PAPR) reduction for orthogonal frequency-division multiplexing (OFDM) based large-scale multiple-input multipleoutput (MIMO) systems. A novel perturbation-assisted scheme is developed to reduce the PAPRs of the transmitted signals by exploiting the redundant degrees-of-freedom (DoFs) inherent in the large-scale antenna array. Specifically, we introduce artificial perturbation signals to the frequency-domain precoded signals, with the aim of reducing the PAPRs of their time-domain counterpart signals. Meanwhile, the additive perturbation signal associated with each tone is constrained to lie in the null-space of its associated channel matrix, such that it does not cause any multi-user inference or out-of-band radiations. Such a problem is formulated as a convex optimization problem, and an efficient algorithm is developed by resorting to the variable splitting and alterative direction method of multipliers (ADMM) techniques. Simulation results show that the proposed method has a fast convergence rate and achieves substantial PAPR reduction within only tens of iterations. In addition, unlike other precoding-based PAPR reduction methods, our proposed method which introduces perturbation signals to the precoded signals is independent of the precoding stage and thus could be more suitable for practical systems.

BackgroundAutologous urothelial cells are often obtained via bladder biopsy to generate the bio-engineered urethra or bladder, while urine-derived stem cells (USC) can be obtained by a non-invasive approach. The objective of this study is to develop an optimal strategy for urothelium with permeability barrier properties using human USC which could be used for tissue repair in the urinary tract system.MethodsUSC were harvested from six healthy adult individuals. To optimize urothelial differentiation, five different differentiation methods were studied. The induced cells were assessed for gene and protein expression markers of urothelial cells via RT-PCR, Western blotting, and immunofluorescent staining. Barrier function and ultrastructure of the tight junction were assessed with permeability assays and transmission electron microscopy (TEM). Induced cells were both cultured on trans-well membranes and small intestinal submucosa, then investigated under histology analysis.ResultsDifferentiated USC expressed significantly higher levels of urothelial-specific transcripts and proteins (Uroplakin III and Ia), epithelial cell markers (CK20 and AE1/AE3), and tight junction markers (ZO-1, ZO-2, E-cadherin, and Cingulin) in a time-dependent manner, compared to non-induced USC. In vitro assays using fluorescent dye demonstrated a significant reduction in permeability of differentiated USC. In addition, transmission electron microscopy confirmed appropriate ultrastructure of urothelium differentiated from USC, including tight junction formation between neighboring cells, which was similar to positive controls. Furthermore, multilayered urothelial tissues formed 2 weeks after USC were differentiated on intestine submucosal matrix.ConclusionThe present study illustrates an optimal strategy for the generation of differentiated urothelium from stem cells isolated from the urine. The induced urothelium is phenotypically and functionally like native urothelium and has proposed uses in in vivo urological tissue repair or in vitro urethra or bladder modeling.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1035-6) contains supplementary material, which is available to authorized users.

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The mechanism of doxycycline-mediated inhibition of angiogenesis occurs through MMP inhibitory activity and modulation of the PI3K/Akt-eNOS pathway, an MMP-independent mechanism.

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