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      Safety and efficacy of the mesenchymal stem cell in feline eosinophilic keratitis treatment

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          Abstract

          Background

          Feline eosinophilic keratitis (FEK) is a chronic keratopathy caused by a suspected immune mediated response to an unknown antigenic stimulus. The purpose of this study was to investigate the safety and therapeutic effects of allogeneic feline adipose-derived mesenchymal stromal cells (fAd-MSCs) implanted subconjunctival around the ocular surface lesion in five cats with FEK refractory to current available treatments.

          Results

          FEK was diagnosed by clinical appearance and evidence of eosinophil and/or mast cells in corneal cytology. Each animal was treated with two applications of 2 × 10 6 million of fAd-MSCs 2 months apart. Ocular surface integrity was assessed before treatment and at 1, 3, 6 and 11 months after treatment. Clinical signs showed a significant change during the follow-up with resolution of the corneal and conjunctiva lesions and there were no signs of regression or worsening.

          Conclusions

          Implanted cells were well-tolerated and effective reducing clinical signs of FEK with a sustained effect during the study period. None of the animals showed systemic or local complications during the study. To our knowledge, this is the first time in literature that local implantation of allogeneic fAd-MSCs has been found as an effective therapeutic alternative to treat cats with FEK.

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          Most cited references43

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          Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.

          Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.
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            Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation

            Recent advances in understanding the cellular and molecular signaling pathways and global transcriptional regulators of adult mesenchymal stem cells have provided new insights into their biology and potential clinical applications, particularly for tissue repair and regeneration. This review focuses on these advances, specifically in the context of self-renewal and regulation of lineage-specific differentiation of mesenchymal stem cells. In addition we review recent research on the concept of stem cell niche, and its relevance to adult mesenchymal stem cells.
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              Review of the adipose derived stem cell secretome.

              Recent advances in protein detection and analysis have lead to multiple in depth studies that analyze the adipose-derived stem cell (ASC) secretome. These studies differ significantly in their methods of secretome preparation and analysis. Most of them use a pro-differentiation or pro-inflammatory stimulus to observe differential expression of secreted proteins. In spite of the variance in methodologies used, 68 proteins are reported to be commonly expressed in a majority of the studies and may serve as potential candidates for conserved secretome proteins. Multiple recent clinical and basic science studies demonstrate the beneficial role played by secreted proteins in augmenting ASC effects in scenarios involving angiogenesis, wound healing, tissue regeneration and immunomodulation. Furthermore, 3-D formulations of ASCs that preserve the niche environment of cells and their secreted proteins have also shown enhanced clinical effects. In light of the lack of uniformity in prior secretome-analysis studies, and the growing clinical importance of the ASC secretome, more in depth studies that use uniform and standardized means of protein detection and analysis are necessary. Copyright © 2013 Elsevier Masson SAS. All rights reserved.
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                Author and article information

                Contributors
                antoniojvillatoro@gmail.com
                silviacg@uma.es
                vivianafdezgen@gmail.com
                alcoholado@uma.es
                immunestem@immunestem.com
                aboiso@hotmail.com
                becerra@uma.es
                +34 952 131872 , andrades@uma.es
                Journal
                BMC Vet Res
                BMC Vet. Res
                BMC Veterinary Research
                BioMed Central (London )
                1746-6148
                27 March 2018
                27 March 2018
                2018
                : 14
                : 116
                Affiliations
                [1 ]ImmuneStem, Instituto de Inmunología Clínica y Terapia Celular, 29018 Málaga, Spain
                [2 ]ISNI 0000 0001 2298 7828, GRID grid.10215.37, Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, , Faculty of Sciences, University of Málaga, Biomedicine Research Institute of Malaga (IBIMA), ; Campus Universitario de Teatinos, 29071 Málaga, Spain
                [3 ]Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
                [4 ]Hospital veterinario Alhaurín el Grande. Alhaurín el Grande, 29120 Málaga, Spain
                [5 ]Laboratory of Bioengineering and Tissue Regeneration, Andalusian Center for Nanomedicine and Biotechnology-BIONAND, 29590 Málaga, Spain
                Article
                1413
                10.1186/s12917-018-1413-4
                5870249
                29291752
                18ff82ab-745b-4933-ba12-86f8c75a3467
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 18 March 2016
                : 6 March 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100006280, Ministerio de Ciencia y Tecnología;
                Award ID: BIO2015-66266-R
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: FIS PI13/00666
                Funded by: FundRef http://dx.doi.org/10.13039/501100006461, Agencia de Innovación y Desarrollo de Andalucía;
                Award ID: P11-CVI 07245, PAIDI BIO-217
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Veterinary medicine
                cat,adipose mesenchymal stem cell,lacrimal gland,feline eosinophilic keratitis,feline herpes virus,allogeneic cell therapy

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