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      Concise Review: Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine

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          Abstract

          Mesenchymal stem cells (MSC) hold great potential for regenerative medicine because of their ability for self‐renewal and differentiation into tissue‐specific cells such as osteoblasts, chondrocytes, and adipocytes. MSCs orchestrate tissue development, maintenance and repair, and are useful for musculoskeletal regenerative therapies to treat age‐related orthopedic degenerative diseases and other clinical conditions. Importantly, MSCs produce secretory factors that play critical roles in tissue repair that support both engraftment and trophic functions (autocrine and paracrine). The development of uniform protocols for both preparation and characterization of MSCs, including standardized functional assays for evaluation of their biological potential, are critical factors contributing to their clinical utility. Quality control and release criteria for MSCs should include cell surface markers, differentiation potential, and other essential cell parameters. For example, cell surface marker profiles (surfactome), bone‐forming capacities in ectopic and orthotopic models, as well as cell size and granularity, telomere length, senescence status, trophic factor secretion (secretome), and immunomodulation, should be thoroughly assessed to predict MSC utility for regenerative medicine. We propose that these and other functionalities of MSCs should be characterized prior to use in clinical applications as part of comprehensive and uniform guidelines and release criteria for their clinical‐grade production to achieve predictably favorable treatment outcomes for stem cell therapy. S tem C ells T ranslational M edicine 2017;6:2173–2185

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          Most cited references125

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          Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.

          The identity of cells that establish the hematopoietic microenvironment (HME) in human bone marrow (BM), and of clonogenic skeletal progenitors found in BM stroma, has long remained elusive. We show that MCAM/CD146-expressing, subendothelial cells in human BM stroma are capable of transferring, upon transplantation, the HME to heterotopic sites, coincident with the establishment of identical subendothelial cells within a miniature bone organ. Establishment of subendothelial stromal cells in developing heterotopic BM in vivo occurs via specific, dynamic interactions with developing sinusoids. Subendothelial stromal cells residing on the sinusoidal wall are major producers of Angiopoietin-1 (a pivotal molecule of the HSC "niche" involved in vascular remodeling). Our data reveal the functional relationships between establishment of the HME in vivo, establishment of skeletal progenitors in BM sinusoids, and angiogenesis.
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            Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.

            Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. clinicaltrials.gov Identifier: NCT01087996.
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              Mesenchymal progenitor cells in human umbilical cord blood.

              Haemopoiesis is sustained by two main cellular components, the haematopoietic cells (HSCs) and the mesenchymal progenitor cells (MPCs). MPCs are multipotent and are the precursors for marrow stroma, bone, cartilage, muscle and connective tissues. Although the presence of HSCs in umbilical cord blood (UCB) is well known, that of MPCs has been not fully evaluated. In this study, we examined the ability of UCB harvests to generate in culture cells with characteristics of MPCs. Results showed that UCB-derived mononuclear cells, when set in culture, gave rise to adherent cells, which exhibited either an osteoclast- or a mesenchymal-like phenotype. Cells with the osteoclast phenotype were multinucleated, expressed TRAP activity and antigens CD45 and CD51/CD61. In turn, cells with the mesenchymal phenotype displayed a fibroblast-like morphology and expressed several MPC-related antigens (SH2, SH3, SH4, ASMA, MAB 1470, CD13, CD29 and CD49e). Our results suggest that preterm, as compared with term, cord blood is richer in mesenchymal progenitors, similar to haematopoietic progenitors.
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                Author and article information

                Contributors
                vanwijnen.andre@mayo.edu
                Simon.Cool@imb.a-star.edu.sg
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley and Sons Inc. (Hoboken )
                2157-6564
                2157-6580
                26 October 2017
                December 2017
                : 6
                : 12 ( doiID: 10.1002/sct3.2017.6.issue-12 )
                : 2173-2185
                Affiliations
                [ 1 ] Glycotherapeutics Group Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR) Singapore
                [ 2 ] Department of Biomedical Engineering National University of Singapore Singapore
                [ 3 ] Department of Orthopaedic Surgery Mayo Clinic Rochester Minnesota USA
                [ 4 ] Center for Cell Biology and Tissue Engineering, Competence Center for Tissue Engineering and Substance Testing (TEDD) Institute for Chemistry and Biotechnology, ZHAW School of Life Sciences and Facility Management, Zurich University of Applied Sciences Switzerland
                [ 5 ] Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine National University of Singapore Singapore
                Author notes
                [*] [* ]Correspondence: Simon Cool, Ph.D., Institute of Medical Biology, Agency for Science, Technology and Research, 8A Biomedical Grove, Immunos 06‐06, Biopolis, Singapore 138648. Telephone: +65 6407 0176; e‐mail: Simon.Cool@ 123456imb.a-star.edu.sg ; or Andre van Wijnen, Ph.D., Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Medical Sciences Building 3‐69, Rochester, Minnesota 55905, USA. Telephone: 1‐507‐293‐2105; e‐mail: vanwijnen.andre@ 123456mayo.edu
                Author information
                http://orcid.org/0000-0001-8804-8284
                http://orcid.org/0000-0002-4458-0946
                http://orcid.org/0000-0001-8543-3056
                Article
                SCT312233
                10.1002/sctm.17-0129
                5702523
                29076267
                e56a5308-afaf-4d41-8bbb-c423f6299772
                © 2017 The Authors S tem C ells T ranslational M edicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 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
                : 17 May 2017
                : 17 August 2017
                Page count
                Figures: 5, Tables: 1, Pages: 13, Words: 12300
                Funding
                Funded by: NUS Research Scholarship
                Funded by: NMRC
                Funded by: A*STAR
                Funded by: NIH
                Award ID: AR049069
                Funded by: Mayo Clinic Center of Regenerative Medicine
                Categories
                Tissue Engineering and Regenerative Medicine
                Adult Stem Cells
                Mesenchymal Stem Cells
                Bone Marrow Stem Cells
                Aging
                Cell Surface Markers
                Stem Cell Niche
                Technological Advancements
                Tissue Engineering and Regenerative Medicine
                Translational Research Articles and Reviews
                Tissue Engineering and Regenerative Medicine
                Custom metadata
                2.0
                sct312233
                December 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.6.1 mode:remove_FC converted:26.11.2017

                mesenchymal stem/stromal cells,bone marrow,characterization,release criteria,regenerative medicine

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