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      Mesenchymal stromal cells derived from whole human umbilical cord exhibit similar properties to those derived from Wharton's jelly and bone marrow

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          Abstract

          Mesenchymal stromal cells (MSC) can be isolated from several regions of human umbilical cords, including Wharton's jelly (WJ), artery, vein or cord lining. These MSC appear to be immune privileged and are promising candidates for cell therapy. However, isolating MSC from WJ, artery, vein or cord lining requires time‐consuming tissue dissection. MSC can be obtained easily via briefly digesting complete segments of the umbilical cord, likely containing heterogenous or mixed populations of MSC (MC‐MSC). MC‐MSC are generally less well characterized than WJ‐MSC, but nevertheless represent a potentially valuable population of MSC. This study aimed to further characterize MC‐MSC in comparison to WJ‐MSC and also the better‐characterized bone marrow‐derived MSC (BM‐MSC). MC‐MSC proliferated faster, with significantly faster doubling times reaching passage one 8.8 days sooner and surviving longer in culture than WJ‐MSC. All MSC retained the safety aspect of reducing telomere length with increasing passage number. MSC were also assessed for their ability to suppress T‐cell proliferation and for the production of key markers of pluripotency, embryonic stem cells, tolerogenicity (CD40, CD80, CD86 and HLA‐DR) and immunomodulation (indoleamine 2,3‐dioxygenase [IDO] and HLA‐G). The MC‐MSC population displayed all of the positive attributes of WJ‐MSC and BM‐MSC, but they were more efficient to obtain and underwent more population doublings than from WJ, suggesting that MC‐MSC are promising candidates for allogeneic cell therapy in regenerative medicine.

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          Most cited references31

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          Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.

          Human marrow stromal cells (MSCs) can be isolated from bone marrow and differentiate into multiple tissues in vitro and in vivo. These properties make them promising tools in cell and gene therapy. The lack of a specific MSC marker and the low frequency of MSCs in bone marrow necessitate their isolation by in vitro expansion prior to clinical use. This may severely reduce MSC proliferative capacity to the point that the residual proliferative potential is insufficient to maintain long-term tissue regeneration upon reinfusion. In this study we determined the effect of in vitro expansion on the replicative capacity of MSCs by correlating their rate of telomere loss during in vitro expansion with their behavior in vivo. We report that even protocols that involve minimal expansion induce a rapid aging of MSCs, with losses equivalent to about half their total replicative lifespan.
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            IDO-independent suppression of T cell effector function by IFN-γ-licensed human mesenchymal stromal cells.

            Human bone marrow-derived mesenchymal stromal cells (MSCs) inhibit proliferation of activated T cells, and IFN-γ plays an important role in this process. This IFN-γ-licensed veto property is IDO-dependent. To further decipher the mechanistic underpinnings of MSC veto function on T cells, we investigated the effect of MSCs and IFN-γ-licensed MSCs on T cell effector function as assayed by cytokine secretion of T cells. Although MSCs and IFN-γ-licensed MSCs inhibit T cell proliferation, only IFN-γ-licensed MSCs significantly inhibit Th1 cytokine (IFN-γ, TNF-α, and IL-2) production by T cells. Additionally, IFN-γ-licensed MSCs inhibit T cell degranulation as well as single, double, and triple cytokine-producing T cells. Although IFN-γ-licensed MSCs upregulate their IDO activity, we found that MSC IDO catalytic function is dispensable with regard to MSC-driven inhibition of T cell effector function. Novel flow cytometry based functional screening of MSC-expressed, IFN-γ-licensed inhibitory molecules identified B7H1 and B7DC/PD1 pathways as essential effectors in blocking T cell function. Small interfering RNA-mediated blocking of B7H1 and B7DC reverses the inhibitory potential of IFN-γ-licensed MSCs on T cell effector function. Mechanistic analysis revealed that clustering of MHC and coinhibitory molecules are indispensable for the inhibitory effect of IFN-γ MSCs. Although exogenous IL-2 reverses B7H1-Ig-mediated inhibition of T cell proliferation, it does not affect the veto function of IFN-γ MSCs on both T cell proliferation and effector function. Our results reveal a new immunosuppressive property of IFN-γ-licensed MSCs that inhibits T cell effector function independent of IDO but through the ligands for PD1.
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              IFN-γ from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection.

              IFN-γ is necessary in both humans and mice for control of Mycobacterium tuberculosis. CD4 T cells are a significant source of IFN-γ during acute infection in mice and are required for control of bacterial growth and host survival. However, several other types of cells can and do produce IFN-γ during the course of the infection. We sought to determine whether IFN-γ from sources other than CD4 T cells was sufficient to control M. tuberculosis infection and whether CD4 T cells had a role in addition to IFN-γ production. To investigate the role of IFN-γ from CD4 T cells, a murine adoptive transfer model was developed in which all cells were capable of producing IFN-γ, with the exception of CD4 T cells. Our data in this system support that CD4 T cells are essential for control of infection, but also that IFN-γ from CD4 T cells is necessary for host survival and optimal long-term control of bacterial burden. In addition, IFN-γ from CD4 T cells was required for a robust CD8 T cell response. IFN-γ from T cells inhibited intracellular replication of M. tuberculosis in macrophages, suggesting IFN-γ may be necessary for intracellular bactericidal activity. Thus, although CD4 T cells play additional roles in the control of M. tuberculosis infection, IFN-γ is a major function by which these cells participate in resistance to tuberculosis.
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                Author and article information

                Contributors
                sally.roberts@rjah.nhs.uk
                Journal
                FEBS Open Bio
                FEBS Open Bio
                10.1002/(ISSN)2211-5463
                FEB4
                FEBS Open Bio
                John Wiley and Sons Inc. (Hoboken )
                2211-5463
                08 October 2016
                November 2016
                : 6
                : 11 ( doiID: 10.1002/feb4.2016.6.issue-11 )
                : 1054-1066
                Affiliations
                [ 1 ] The Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Foundation Trust & Institute of Science & Technology in Medicine Keele University Oswestry ShropshireUK
                [ 2 ] Laboratory of Cell Proliferation and Ageing Institute of Biosciences and ApplicationsNational Centre for Scientific Research “Demokritos” AthensGreece
                Author notes
                [*] [* ] Correspondence

                S. Roberts, The Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, ISTM & Keele University, Oswestry, SY10 7AG, UK

                E‐mail: sally.roberts@ 123456rjah.nhs.uk

                Article
                FEB412104
                10.1002/2211-5463.12104
                5095143
                27833846
                a8c1ea18-0a58-459d-9f5a-3f90ed482131
                © 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 31 December 2015
                : 27 May 2016
                : 20 July 2016
                Page count
                Figures: 4, Tables: 1, Pages: 13, Words: 9267
                Funding
                Funded by: Arthritis Research UK Tissue Engineering Centre
                Award ID: 19429
                Award ID: 20253
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                feb412104
                November 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.6 mode:remove_FC converted:04.11.2016

                allogeneic cell therapy,bone marrow‐derived mesenchymal stromal cells,immunomodulation,umbilical cord‐derived mesenchymal stromal cells

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