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      Adipose, Bone Marrow and Synovial Joint-Derived Mesenchymal Stem Cells for Cartilage Repair

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          Abstract

          Current cell-based repair strategies have proven unsuccessful for treating cartilage defects and osteoarthritic lesions, consequently advances in innovative therapeutics are required and mesenchymal stem cell-based (MSC) therapies are an expanding area of investigation. MSCs are capable of differentiating into multiple cell lineages and exerting paracrine effects. Due to their easy isolation, expansion, and low immunogenicity, MSCs are an attractive option for regenerative medicine for joint repair. Recent studies have identified several MSC tissue reservoirs including in adipose tissue, bone marrow, cartilage, periosteum, and muscle. MSCs isolated from these discrete tissue niches exhibit distinct biological activities, and have enhanced regenerative potentials for different tissue types. Each MSC type has advantages and disadvantages for cartilage repair and their use in a clinical setting is a balance between expediency and effectiveness. In this review we explore the challenges associated with cartilage repair and regeneration using MSC-based cell therapies and provide an overview of phenotype, biological activities, and functional properties for each MSC population. This paper also specifically explores the therapeutic potential of each type of MSC, particularly focusing on which cells are capable of producing stratified hyaline-like articular cartilage regeneration. Finally we highlight areas for future investigation. Given that patients present with a variety of problems it is unlikely that cartilage regeneration will be a simple “one size fits all,” but more likely an array of solutions that need to be applied systematically to achieve regeneration of a biomechanically competent repair tissue.

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          Most cited references 156

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          Osteoarthritis.

          Osteoarthritis (OA) is characterized by degeneration of articular cartilage, limited intraarticular inflammation with synovitis, and changes in peri-articular and subchondral bone. Multiple factors are involved in the pathogenesis of OA, including mechanical influences, the effects of aging on cartilage matrix composition and structure, and genetic factors. Since the initial stages of OA involve increased cell proliferation and synthesis of matrix proteins, proteinases, growth factors, cytokines, and other inflammatory mediators by chondrocytes, research has focused on the chondrocyte as the cellular mediator of OA pathogenesis. The other cells and tissues of the joint, including the synovium and subchondral bone, also contribute to pathogenesis. The adult articular chondrocyte, which normally maintains the cartilage with a low turnover of matrix constituents, has limited capacity to regenerate the original cartilage matrix architecture. It may attempt to recapitulate phenotypes of early stages of cartilage development, but the precise zonal variations of the original cartilage cannot be replicated. Current pharmacological interventions that address chronic pain are insufficient, and no proven structure-modifying therapy is available. Cartilage tissue engineering with or without gene therapy is the subject of intense investigation. There are multiple animal models of OA, but there is no single model that faithfully replicates the human disease. This review will focus on questions currently under study that may lead to better understanding of mechanisms of OA pathogenesis and elucidation of effective strategies for therapy, with emphasis on mechanisms that affect the function of chondrocytes and interactions with surrounding tissues. 2007 Wiley-Liss, Inc.
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            Fibroblast precursors in normal and irradiated mouse hematopoietic organs.

            Using the in vitro colony assay, clonogenic fibroblast precursor cells (CFU-F) were detected in the bone marrow, spleen and thymus from adult mice. The survival curve for CFU-F of mouse bone marrow irradiated in vitro has a D0 of 220 r. Regeneration of bone marrow CFU-F after whole-body irradiation with 150 r is characterized by a marked secondary loss and post-irradiation lag and dip, lasting 6 days, followed by return to normal values by about the 25th day. This pattern of post-radiation recovery of CFU-F is similar to that of the CFU-s. In addition, during the first 6 hours following irradiation the number of CFU-F increased approximately twofold.
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              Why are MSCs therapeutic? New data: new insight.

              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
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                20 December 2016
                2016
                : 7
                Affiliations
                1Faculty of Health and Medical Sciences, University of Surrey Guildford, UK
                2Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen Debrecen, Hungary
                3Centre for NanoHealth, Swansea University Medical School Swansea, UK
                4Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Queen's Medical Centre Nottingham, UK
                5King Fahd Medical Research Center, King AbdulAziz University Jeddah, Saudi Arabia
                6Sheik Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis with Stem Cells, King AbdulAziz University Jeddah, Saudi Arabia
                Author notes

                Edited by: Francesco De Francesco, Seconda Università degli Studi di Napoli, Italy

                Reviewed by: Virginia Tirino, Seconda Università degli Studi di Napoli, Italy; Shiro Jimi, Fukuoka University, Japan

                *Correspondence: Ali Mobasheri a.mobasheri@ 123456surrey.ac.uk

                This article was submitted to Stem Cell Research, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2016.00213
                5167763
                Copyright © 2016 Fellows, Matta, Zakany, Khan and Mobasheri.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 215, Pages: 20, Words: 17825
                Funding
                Funded by: European Commission 10.13039/501100000780
                Award ID: 305815
                Award ID: 625746
                Award ID: 115770
                Funded by: Arthritis Research UK 10.13039/501100000341
                Award ID: 20194
                Award ID: 21076
                Funded by: Deanship of Scientific Research, King Faisal University 10.13039/501100004686
                Categories
                Genetics
                Review

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