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      Cell‐Based Therapies: The Nonresponder

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      1 ,
      Stem Cells Translational Medicine
      John Wiley & Sons, Inc.

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          Summary

          Cell‐based therapies have come of age and several phase III trials are now being conducted. Cell‐based therapies, especially involving mesenchymal stem cells (MSCs), have substantial nonresponder rates, as has been reported in some current clinical trials. This high rate is expected as the MSCs are neither tuned for each of the diseases that are being treated nor for the huge variance in the genetics and response characteristics of the individual patients being treated. Such nonresponders might be used as a control group, thus eliminating the need for placebo controls. stem cells translational medicine 2018;7:762–766

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          Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities

          Mesenchymal stromal cells (MSCs) have been the subject of clinical trials for more than a generation, and the outcomes of advanced clinical trials have fallen short of expectations raised by encouraging pre-clinical animal data in a wide array of disease models. In this Perspective, important biological and pharmacological disparities in pre-clinical research and human translational studies are highlighted, and analyses of clinical trial failures and recent successes provide a rational pathway to MSC regulatory approval and deployment for disorders with unmet medical needs.
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            Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1.

            Murine IgM monoclonal antibody STRO-1 identifies a cell surface antigen expressed by stromal elements in human bone marrow (BM). STRO-1 binds to approximately 10% of BM mononuclear cells, greater than 95% of which are nucleated erythroid precursors, but does not react with committed progenitor cells (colony-forming unit granulocyte-macrophage [CFU-GM], erythroid bursts [BFU-E], and mixed colonies [CFU-Mix]). Fibroblast colony-forming cells (CFU-F) are present exclusively in the STRO-1+ population. Dual-color cell sorting using STRO-1 in combination with antibody to glycophorin A yields a population approximately 100-fold enriched in CFU-F in the STRO-1+/glycophorin A- population. When plated under long-term BM culture (LTBMC) conditions, STRO-1+ cells generate adherent cell layers containing multiple stromal cell types, including adipocytes, smooth muscle cells, and fibroblastic elements. STRO-1+ cells isolated from LTBMC at later times retain the capacity to generate adherent layers with a cellular composition identical to that of the parent cultures. The STRO-1-selected adherent layers are able to support the generation of clonogenic cells and mature hematopoietic cells from a population of CD34+ cells highly enriched in so-called long-term culture-initiating cells. We conclude that antibody STRO-1 binds to BM stromal elements with the capacity to transfer the hematopoietic microenvironment in vitro.
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              Natural history of mesenchymal stem cells, from vessel walls to culture vessels.

              Mesenchymal stem/stromal cells (MSCs) can regenerate tissues by direct differentiation or indirectly by stimulating angiogenesis, limiting inflammation, and recruiting tissue-specific progenitor cells. MSCs emerge and multiply in long-term cultures of total cells from the bone marrow or multiple other organs. Such a derivation in vitro is simple and convenient, hence popular, but has long precluded understanding of the native identity, tissue distribution, frequency, and natural role of MSCs, which have been defined and validated exclusively in terms of surface marker expression and developmental potential in culture into bone, cartilage, and fat. Such simple, widely accepted criteria uniformly typify MSCs, even though some differences in potential exist, depending on tissue sources. Combined immunohistochemistry, flow cytometry, and cell culture have allowed tracking the artifactual cultured mesenchymal stem/stromal cells back to perivascular anatomical regions. Presently, both pericytes enveloping microvessels and adventitial cells surrounding larger arteries and veins have been described as possible MSC forerunners. While such a vascular association would explain why MSCs have been isolated from virtually all tissues tested, the origin of the MSCs grown from umbilical cord blood remains unknown. In fact, most aspects of the biology of perivascular MSCs are still obscure, from the emergence of these cells in the embryo to the molecular control of their activity in adult tissues. Such dark areas have not compromised intents to use these cells in clinical settings though, in which purified perivascular cells already exhibit decisive advantages over conventional MSCs, including purity, thorough characterization and, principally, total independence from in vitro culture. A growing body of experimental data is currently paving the way to the medical usage of autologous sorted perivascular cells for indications in which MSCs have been previously contemplated or actually used, such as bone regeneration and cardiovascular tissue repair.
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                Author and article information

                Contributors
                arnold.caplan@case.edu
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                2157-6564
                2157-6580
                25 September 2018
                November 2018
                : 7
                : 11 ( doiID: 10.1002/sct3.2018.7.issue-11 )
                : 762-766
                Affiliations
                [ 1 ] Department of Biology, Skeletal Research Center Case Western Reserve University Cleveland Ohio USA
                Author notes
                [*] [* ] Correspondence: Arnold I. Caplan, Ph.D., Department of Biology, Skeletal Research Center, Case Western Reserve University, 10600 Euclid Avenue, Cleveland, Ohio 44106, USA. Telephone: 216‐368‐3562; e‐mail: arnold.caplan@ 123456case.edu

                Author information
                http://orcid.org/0000-0002-8677-6621
                Article
                SCT312388
                10.1002/sctm.18-0074
                6216418
                30251411
                01b15b81-4896-4656-ae4b-866158cbf2eb
                © 2018 The Authors. stem cells translational medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 27 March 2018
                : 24 June 2018
                : 10 July 2018
                Page count
                Figures: 1, Tables: 0, Pages: 5, Words: 4694
                Funding
                Funded by: Virginia and David Baldwin Fund
                Funded by: National Institutes of Health
                Award ID: 1P41EB021911‐01
                Categories
                Perspectives
                Perspectives
                Custom metadata
                2.0
                sct312388
                November 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.1 mode:remove_FC converted:05.11.2018

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