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      Polysaccharide Hydrogel Combined with Mesenchymal Stem Cells Promotes the Healing of Corneal Alkali Burn in Rats

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          Abstract

          Corneal chemical burns are common ophthalmic injuries that may result in permanent visual impairment. Although significant advances have been achieved on the treatment of such cases, the structural and functional restoration of a chemical burn-injured cornea remains challenging. The applications of polysaccharide hydrogel and subconjunctival injection of mesenchymal stem cells (MSCs) have been reported to promote the healing of corneal wounds. In this study, polysaccharide was extracted from Hardy Orchid and mesenchymal stem cells (MSCs) were derived from Sprague-Dawley rats. Supplementation of the polysaccharide significantly enhanced the migration rate of primarily cultured rat corneal epithelial cells. We examined the therapeutic effects of polysaccharide in conjunction with MSCs application on the healing of corneal alkali burns in rats. Compared with either treatment alone, the combination strategy resulted in significantly better recovery of corneal epithelium and reduction in inflammation, neovascularization and opacity of healed cornea. Polysaccharide and MSCs acted additively to increase the expression of anti-inflammatory cytokine (TGF-β), antiangiogenic cytokine (TSP-1) and decrease those promoting inflammation (TNF-α), chemotaxis (MIP-1α and MCP-1) and angiogenesis (VEGF and MMP-2). This study provided evidence that Hardy Orchid derived polysaccharide and MSCs are safe and effective treatments for corneal alkali burns and that their benefits are additive when used in combination. We concluded that combination therapy with polysaccharide and MSCs is a promising clinical treatment for corneal alkali burns and may be applicable for other types of corneal disorder.

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          Hydrogels for tissue engineering.

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            Mouse Bone Marrow-Derived Mesenchymal Stromal Cells Turn Activated Macrophages into a Regulatory-Like Profile

            In recent years it has become clear that the therapeutic properties of bone marrow-derived mesenchymal stromal cells (MSC) are related not only to their ability to differentiate into different lineages but also to their capacity to suppress the immune response. We here studied the influence of MSC on macrophage function. Using mouse thioglycolate-elicited peritoneal macrophages (M) stimulated with LPS, we found that MSC markedly suppressed the production of the inflammatory cytokines TNF-α, IL-6, IL-12p70 and interferon-γ while increased the production of IL-10 and IL-12p40. Similar results were observed using supernatants from MSC suggesting that factor(s) constitutively released by MSC are involved. Supporting a role for PGE2 we observed that acetylsalicylic acid impaired the ability of MSC to inhibit the production of inflammatory cytokines and to stimulate the production of IL-10 by LPS-stimulated M. Moreover, we found that MSC constitutively produce PGE2 at levels able to inhibit the production of TNF-α and IL-6 by activated M. MSC also inhibited the up-regulation of CD86 and MHC class II in LPS-stimulated M impairing their ability to activate antigen-specific T CD4+ cells. On the other hand, they stimulated the uptake of apoptotic thymocytes by M. Of note, MSC turned M into cells highly susceptible to infection with the parasite Trypanosoma cruzi increasing more than 5-fold the rate of M infection. Using a model of inflammation triggered by s.c. implantation of glass cylinders, we found that MSC stimulated the recruitment of macrophages which showed a low expression of CD86 and the MHC class II molecule Iab and a high ability to produce IL-10 and IL-12p40, but not IL-12 p70. In summary, our results suggest that MSC switch M into a regulatory profile characterized by a low ability to produce inflammatory cytokines, a high ability to phagocyte apoptotic cells, and a marked increase in their susceptibility to infection by intracellular pathogens.
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              The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury.

              To investigate the anti-inflammatory and anti-angiogenic effects of mesenchymal stem cells (MSC) in the chemically burned corneas, we mechanically removed the corneal epithelium of rats after 100% alcohol instillation. The rats were then randomized into four groups: fresh media, conditioned media derived from the MSC culture (MSC-CM), MSC applied topically to the damaged corneas for 2 hours immediately after the injury or MSC-CM applied either once or 3 times per day for 3 consecutive days. Corneal surface was evaluated every week. After 3 weeks, the corneas were stained with the hematoxylin-eosin, and the expression of interleukin (IL)-2, interferon (IFN)-gamma, IL-6, IL-10, transforming growth factor (TGF)-beta1, thrombospondin-1 (TSP-1), matrix metalloproteinase-2 (MMP-2), and vascular endothelial growth factor (VEGF) were analyzed. CD4+ cells were assessed in the corneas. We found that both MSC and three-time applied MSC-CM (1) reduced corneal inflammation and neovascularization, (2) decreased IL-2 and IFN-gamma, although increased IL-10 and TGF-beta1 as well as IL-6, (3) reduced the infiltration of CD4+ cells, and (4) upregulated the expression of TSP-1, although downregulated that of MMP-2. Interestingly, whereas three-time application of MSC-CM was partially effective, transplantation of MSC achieved a better outcome in suppressing corneal inflammation. The results of this study suggest that the anti-inflammatory and anti-angiogenic action of MSC in the chemically burned corneas might be mediated in part through paracrine pathways involving soluble factors such as IL-10, TGF-beta1, IL-6 and TSP-1.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 March 2015
                2015
                : 10
                : 3
                : e0119725
                Affiliations
                [1 ]TianjinMedical University Eye Hospital, The College of Optometry,Tianjin Medical University Eye Institute, Tianjin, China
                [2 ]School of Public Health, Tianjin Medical University, Tianjin, China
                Cedars Sinai Medical Center, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CY X. Li. Performed the experiments: YK YW XC X. Liu MY. Analyzed the data: YK YW XC CY. Contributed reagents/materials/analysis tools: YK YW XC CY. Wrote the paper: YK YW CY X. Li.

                Article
                PONE-D-14-26115
                10.1371/journal.pone.0119725
                4366244
                25789487
                c24ec6e7-cb98-456a-b7b7-d6ca36411e70
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 24 June 2014
                : 25 January 2015
                Page count
                Figures: 7, Tables: 0, Pages: 18
                Funding
                Supported by the grant from National Sciences Foundation of China (81371037); http://www.nsfc.gov.cn/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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