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      Mesenchymal Stromal Cell-Based Therapies as Promising Treatments for Muscle Regeneration After Snakebite Envenoming

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          Abstract

          Snakebite envenoming is a global neglected disease with an incidence of up to 2.7 million new cases every year. Although antivenoms are so-far the most effective treatment to reverse the acute systemic effects induced by snakebite envenoming, they have a limited therapeutic potential, being unable to completely neutralize the local venom effects. Local damage, such as dermonecrosis and myonecrosis, can lead to permanent sequelae with physical, social, and psychological implications. The strong inflammatory process induced by snake venoms is associated with poor tissue regeneration, in particular the lack of or reduced skeletal muscle regeneration. Mesenchymal stromal cells (MSCs)-based therapies have shown both anti-inflammatory and pro-regenerative properties. We postulate that using allogeneic MSCs or their cell-free products can induce skeletal muscle regeneration in snakebite victims, improving all the three steps of the skeletal muscle regeneration process, mainly by anti-inflammatory activity, paracrine effects, neovascularization induction, and inhibition of tissue damage, instrumental for microenvironment remodeling and regeneration. Since snakebite envenoming occurs mainly in areas with poor healthcare, we enlist the principles and potential of MSCs-based therapies and discuss regulatory issues, good manufacturing practices, transportation, storage, and related-procedures that could allow the administration of these therapies, looking forward to a safe and cost-effective treatment for a so far unsolved and neglected health problem.

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          Most cited references128

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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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            Multilineage potential of adult human mesenchymal stem cells.

            Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
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              Concise Review: MSC-Derived Exosomes for Cell-Free Therapy.

              Mesenchymal stem cell transplantation is undergoing extensive evaluation as a cellular therapy in human clinical trials. Because MSCs are easily isolated and amenable to culture expansion in vitro there is a natural desire to test MSCs in many diverse clinical indications. This is exemplified by the rapidly expanding literature base that includes many in vivo animal models. More recently, MSC-derived extracellular vesicles (EVs), which include exosomes and microvesicles (MV), are being examined for their role in MSC-based cellular therapy. These vesicles are involved in cell-to-cell communication, cell signaling, and altering cell or tissue metabolism at short or long distances in the body. The exosomes and MVs can influence tissue responses to injury, infection, and disease. MSC-derived exosomes have a content that includes cytokines and growth factors, signaling lipids, mRNAs, and regulatory miRNAs. To the extent that MSC exosomes can be used for cell-free regenerative medicine, much will depend on the quality, reproducibility, and potency of their production, in the same manner that these parameters dictate the development of cell-based MSC therapies. However, the MSC exosome's contents are not static, but rather a product of the MSC tissue origin, its activities and the immediate intercellular neighbors of the MSCs. As such, the exosome content produced by MSCs appears to be altered when MSCs are cultured with tumor cells or in the in vivo tumor microenvironment. Therefore, careful attention to detail in producing MSC exosomes may provide a new therapeutic paradigm for cell-free MSC-based therapies with decreased risk. Stem Cells 2017;35:851-858.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                03 February 2021
                2020
                : 11
                : 609961
                Affiliations
                [1] 1 Faculty of Biological Sciences, Universidad Nacional Mayor de San Marcos , Lima, Peru
                [2] 2 Institute of Tropical Diseases, Universidad Nacional Toribio Rodríguez de Mendoza de Amazonas , Chachapoyas, Peru
                [3] 3 Faculty of Medicine, Universidad Privada San Juan Bautista , Lima, Peru
                [4] 4 Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide , Seville, Spain
                [5] 5 Department of Surgery, Fundación Jiménez Díaz, Unidad de Terapias Avanzadas, Universidad Autónoma de Madrid , Madrid, Spain
                [6] 6 ISABIAL-Hospital General y Universitario de Alicante , Alicante, Spain
                [7] 7 Departmento de Fisica Aplicadas, University Miguel Hernández , Alicante, Spain
                [8] 8 Department of Cell Regeneration and Advanced Therapies, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University of Pablo de Olavide-University of Sevilla-CSIC , Seville, Spain
                [9] 9 Biomedical Research Network for Diabetes and Related Metabolic Diseases—CIBERDEM, Instituto de Salud Carlos III , Madrid, Spain
                [10] 10 Center of Research and Development, Fundação Ezequiel Dias , Belo Horizonte, Brazil
                [11] 11 Departament of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais , Belo Horizonte, Brazil
                [12] 12 Institute of Bioengineering, University Miguel Hernandez de Elche , Alicante, Spain
                Author notes

                Edited by: Wuelton Monteiro, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Brazil

                Reviewed by: Juliana Zuliani, Oswaldo Cruz Foundation (Fiocruz), Brazil; José María Gutiérrez, University of Costa Rica, Costa Rica

                *Correspondence: Carlos Chávez-Olórtegui, olortegi@ 123456icb.ufmg.br ; Juan R. Tejedo, jrtejhua@ 123456upo.es

                This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.609961
                7902043
                33633730
                b9298965-5baa-40ba-b397-784e2ba626e6
                Copyright © 2021 Sanchez-Castro, Pajuelo-Reyes, Tejedo, Soria-Juan, Tapia-Limonchi, Andreu, Hitos, Martin, Cahuana, Guerra-Duarte, de Assis, Bedoya, Soria, Chávez-Olórtegui and Tejedo

                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) and the copyright owner(s) 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.

                History
                : 24 September 2020
                : 17 December 2020
                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 128, Pages: 17, Words: 7489
                Funding
                Funded by: Fondo Nacional de Desarrollo Científico y Tecnológico 10.13039/501100002850
                Categories
                Immunology
                Review

                Immunology
                advanced therapy medicinal products,mesenchymal stromal cells,snakebite,envenoming,muscle regeneration

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