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      Concise Review: Exploring Immunomodulatory Features of Mesenchymal Stromal Cells in Humanized Mouse Models

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          Abstract

          With their immunosuppressive features, human mesenchymal stromal cells (MSCs), sometimes also termed as mesenchymal stem cells, hold great potential as a cell‐based therapy for various immune‐mediated diseases. Indeed, MSCs have already been approved as a treatment for graft versus host disease. However, contradictory data from clinical trials and lack of conclusive proof of efficacy hinder the progress toward wider clinical use of MSCs and highlight the need for more relevant disease models. Humanized mice are increasingly used as models to study immune‐mediated disease, as they simulate human immunobiology more closely than conventional murine models. With further advances in their resemblance to human immunobiology, it is very likely that humanized mice will be used more commonly as models to investigate MSCs with regard to their therapeutic safety and their immunomodulatory effect and its underlying mechanisms. Recent studies that explore the immunosuppressive features of MSCs in humanized mouse models will be discussed in this review. S tem C ells 2019;37:298–305

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          Of mice and not men: differences between mouse and human immunology.

          Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.
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            Humanized mice for immune system investigation: progress, promise and challenges.

            Significant advances in our understanding of the in vivo functions of human cells and tissues and the human immune system have resulted from the development of 'humanized' mouse strains that are based on severely immunodeficient mice with mutations in the interleukin-2 receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analyses of human immune biology, development and functions. In this Review, we discuss recent advances in the development and utilization of humanized mice, the lessons learnt, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology.
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              Why are MSCs therapeutic? New data: new insight.

              A Caplan (2009)
              Adult marrow-derived mesenchymal stem cells (MSCs) are able to differentiate into bone, cartilage, muscle, marrow stroma, tendon-ligament, fat and other connective tissues. The questions can be asked, what do MSCs do naturally and where is the MSC niche? New insight and clinical experience suggest that MSCs are naturally found as perivascular cells, summarily referred to as pericytes, which are released at sites of injury, where they secrete large quantities of bioactive factors that are both immunomodulatory and trophic. The trophic activity inhibits ischaemia-caused apoptosis and scarring while stimulating angiogenesis and the mitosis of tissue intrinsic progenitor cells. The immunomodulation inhibits lymphocyte surveillance of the injured tissue, thus preventing autoimmunity, and allows allogeneic MSCs to be used in a variety of clinical situations. Thus, a new, enlightened era of experimentation and clinical trials has been initiated with xenogenic and allogeneic MSCs.
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                Author and article information

                Contributors
                vera-mehler@t-online.de
                Journal
                Stem Cells
                Stem Cells
                10.1002/(ISSN)1549-4918
                STEM
                Stem Cells (Dayton, Ohio)
                John Wiley & Sons, Inc. (Hoboken, USA )
                1066-5099
                1549-4918
                21 December 2018
                March 2019
                : 37
                : 3 ( doiID: 10.1002/stem.v37.3 )
                : 298-305
                Affiliations
                [ 1 ] Endocrinology Section, Biotherapeutics National Institute for Biological Standards and Control South Mimms United Kingdom
                [ 2 ] Division of Infection and Immunity University College London London United Kingdom
                Author notes
                [*] [* ]Correspondence: Vera J. Mehler, M.Sc., B.Sc., Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control, Blanche Lane, South Mimms EN6 3QG, United Kingdom. Telephone: 44 (0) 1707 641 073; e‐mail: vera-mehler@ 123456t-online.de
                Author information
                https://orcid.org/0000-0003-4614-7393
                Article
                STEM2948
                10.1002/stem.2948
                6446739
                30395373
                d786654d-15f4-4605-b630-c240e4d09759
                © 2018 Crown copyright. stem cells © AlphaMed Press 2018

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 06 July 2018
                : 26 September 2018
                : 25 October 2018
                Page count
                Figures: 2, Tables: 1, Pages: 8, Words: 7095
                Funding
                Funded by: NIHR Policy Research Programme, Regulatory Science Research Unit
                Funded by: UK Department of Health's Policy Research Programme
                Award ID: 044/0069
                Categories
                Translational and Clinical Research
                Translational and Clinical Research
                Custom metadata
                2.0
                stem2948
                March 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:03.04.2019

                Molecular medicine
                humanized mouse,mesenchymal stem cells,cell therapy,immunosuppression,immunomodulation,human immune system,graft versus host disease

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