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      Challenges and perspectives of tendon-derived cell therapy for tendinopathy: from bench to bedside

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          Abstract

          Tendon is composed of dense fibrous connective tissues, connecting muscle at the myotendinous junction (MTJ) to bone at the enthesis and allowing mechanical force to transmit from muscle to bone. Tendon diseases occur at different zones of the tendon, including enthesis, MTJ and midsubstance of the tendon, due to a variety of environmental and genetic factors which consequently result in different frequencies and recovery rates. Self-healing properties of tendons are limited, and cell therapeutic approaches in which injured tendon tissues are renewed by cell replenishment are highly sought after. Homologous use of individual’s tendon-derived cells, predominantly differentiated tenocytes and tendon-derived stem cells, is emerging as a treatment for tendinopathy through achieving minimal cell manipulation for clinical use. This is the first review summarizing the progress of tendon-derived cell therapy in clinical use and its challenges due to the structural complexity of tendons, heterogeneous composition of extracellular cell matrix and cells and unsuitable cell sources. Further to that, novel future perspectives to improve therapeutic effect in tendon-derived cell therapy based on current basic knowledge are discussed.

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          Most cited references197

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          Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

          Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
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            Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

            The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.
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              Development and applications of CRISPR-Cas9 for genome engineering.

              Recent advances in genome engineering technologies based on the CRISPR-associated RNA-guided endonuclease Cas9 are enabling the systematic interrogation of mammalian genome function. Analogous to the search function in modern word processors, Cas9 can be guided to specific locations within complex genomes by a short RNA search string. Using this system, DNA sequences within the endogenous genome and their functional outputs are now easily edited or modulated in virtually any organism of choice. Cas9-mediated genetic perturbation is simple and scalable, empowering researchers to elucidate the functional organization of the genome at the systems level and establish causal linkages between genetic variations and biological phenotypes. In this Review, we describe the development and applications of Cas9 for a variety of research or translational applications while highlighting challenges as well as future directions. Derived from a remarkable microbial defense system, Cas9 is driving innovative applications from basic biology to biotechnology and medicine. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                ziming.chen@research.uwa.edu.au
                peilin.chen@research.uwa.edu.au
                m.zheng93@me.com
                colingjj@163.com
                delin.liu@research.uwa.edu.au
                allanwang@aapt.net.au
                zhengqiujian@gdph.org.cn
                toby@coastalorthopaedics.com
                andrew.tai@perron.uwa.edu.au
                minghao.zheng@uwa.edu.au
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                2 September 2022
                2 September 2022
                2022
                : 13
                : 444
                Affiliations
                [1 ]GRID grid.1012.2, ISNI 0000 0004 1936 7910, Division of Surgery, Centre for Orthopaedic Research, Medical School, , The University of Western Australia, ; Nedlands, WA 6009 Australia
                [2 ]GRID grid.482226.8, ISNI 0000 0004 0437 5686, Perron Institute for Neurological and Translational Science, ; Nedlands, WA 6009 Australia
                [3 ]GRID grid.3521.5, ISNI 0000 0004 0437 5942, Department of Orthopaedic Surgery, , Sir Charles Gairdner Hospital, ; Nedlands, WA 6009 Australia
                [4 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Orthopaedic Surgery, , Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital, ; Shanghai, 200233 China
                [5 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, The Second School of Clinical Medicine, , Southern Medical University, ; Guangzhou, 510000 Guangdong China
                [6 ]GRID grid.410643.4, Department of Orthopedics, Guangdong Provincial People’s Hospital, , Guangdong Academy of Medical Sciences, ; Guangzhou, 510000 Guangdong China
                Author information
                http://orcid.org/0000-0003-1185-4768
                Article
                3113
                10.1186/s13287-022-03113-6
                9438319
                36056395
                c33afde5-004e-4ea1-a439-95157cd7015e
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 7 June 2022
                : 3 August 2022
                Funding
                Funded by: The University of Western Australia
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                Molecular medicine
                tendon,tendon-derived stem cells (tdscs),myotendinous junction (mtj),midsubstance of tendon,enthesis,tendinopathy,tendon-derived cell therapy

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