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      Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies

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          Abstract

          Multipotent mesenchymal stromal cells (MSC) have been widely explored for cell-based therapy of immune-mediated, inflammatory, and degenerative diseases, due to their immunosuppressive, immunomodulatory, and regenerative potentials. Preclinical studies and clinical trials have demonstrated promising therapeutic results although these have been somewhat limited. Aspects such as low in vivo MSC survival in inhospitable disease microenvironments, requirements for ex vivo cell overexpansion prior to infusions, intrinsic differences between MSC and different sources and donors, variability of culturing protocols, and potency assays to evaluate MSC products have been described as limitations in the field. In recent years, priming approaches to empower MSC have been investigated, thereby generating cellular products with improved potential for different clinical applications. Herein, we review the current priming approaches that aim to increase MSC therapeutic efficacy. Priming with cytokines and growth factors, hypoxia, pharmacological drugs, biomaterials, and different culture conditions, as well as other diverse molecules, are revised from current and future perspectives.

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          Most cited references130

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          Indoleamine 2,3 dioxygenase and metabolic control of immune responses.

          Sustained access to nutrients is a fundamental biological need, especially for proliferating cells, and controlling nutrient supply is an ancient strategy to regulate cellular responses to stimuli. By catabolizing the essential amino acid TRP, cells expressing the enzyme indoleamine 2,3 dioxygenase (IDO) can mediate potent local effects on innate and adaptive immune responses to inflammatory insults. Here, we discuss recent progress in elucidating how IDO activity promotes local metabolic changes that impact cellular and systemic responses to inflammatory and immunological signals. These recent developments identify potential new targets for therapy in a range of clinical settings, including cancer, chronic infections, autoimmune and allergic syndromes, and transplantation. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties.

            Previous reports suggested that culture as 3D aggregates or as spheroids can increase the therapeutic potential of the adult stem/progenitor cells referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). Here we used a hanging drop protocol to prepare human MSCs (hMSCs) as spheroids that maximally expressed TNFalpha stimulated gene/protein 6 (TSG-6), the antiinflammatory protein that was expressed at high levels by hMSCs trapped in the lung after i.v. infusion and that largely explained the beneficial effects of hMSCs in mice with myocardial infarcts. The properties of spheroid hMSCs were found to depend critically on the culture conditions. Under optimal conditions for expression of TSG-6, the hMSCs also expressed high levels of stanniocalcin-1, a protein with both antiinflammatory and antiapoptotic properties. In addition, they expressed high levels of three anticancer proteins: IL-24, TNFalpha-related apoptosis inducing ligand, and CD82. The spheroid hMSCs were more effective than hMSCs from adherent monolayer cultures in suppressing inflammatory responses in a coculture system with LPS-activated macrophages and in a mouse model for peritonitis. In addition, the spheroid hMSCs were about one-fourth the volume of hMSCs from adherent cultures. Apparently as a result, larger numbers of the cells trafficked through the lung after i.v. infusion and were recovered in spleen, liver, kidney, and heart. The data suggest that spheroid hMSCs may be more effective than hMSCs from adherent cultures in therapies for diseases characterized by sterile tissue injury and unresolved inflammation and for some cancers that are sensitive to antiinflammatory agents.
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              Use of mesenchymal stem cells for therapy of cardiac disease.

              Despite substantial clinical advances over the past 65 years, cardiovascular disease remains the leading cause of death in America. The past 15 years has witnessed major basic and translational interest in the use of stem and precursor cells as a therapeutic agent for chronically injured organs. Among the cell types under investigation, adult mesenchymal stem cells are widely studied, and in early stage, clinical studies show promise for repair and regeneration of cardiac tissues. The ability of mesenchymal stem cells to differentiate into mesoderm- and nonmesoderm-derived tissues, their immunomodulatory effects, their availability, and their key role in maintaining and replenishing endogenous stem cell niches have rendered them one of the most heavily investigated and clinically tested type of stem cell. Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials. Here, we review the biology of mesenchymal stem cells, their interaction with endogenous molecular and cellular pathways, and their modulation of immune responses. Additionally, we discuss factors that enhance their proliferative and regenerative ability and factors that may hinder their effectiveness in the clinical setting.
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                Author and article information

                Contributors
                nadia.noronha@hotmail.com
                amanda.mizukami@hemocentro.fmrp.usp.br
                caliari.carolina@gmail.com
                cominal@fcfrp.usp.br
                lucasmartins200959@hotmail.com
                dimas@fmrp.usp.br
                kamilla@fcfrp.usp.br
                +55 16 3315-0665 , kelenfarias@fcfrp.usp.br
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                2 May 2019
                2 May 2019
                2019
                : 10
                : 131
                Affiliations
                [1 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, , University of São Paulo, ; Ribeirão Preto, Brazil
                [2 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Graduate Program on Bioscience and Biotechnology, School of Pharmaceutical Sciences of Ribeirão Preto, , University of São Paulo, ; Ribeirão Preto, Brazil
                [3 ]In Situ Cell Therapy, SUPERA Innovation and Technology Park, Ribeirão Preto, São Paulo Brazil
                [4 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Graduate Program on Basic and Applied Immunology, Ribeirão Preto Medical School, , University of São Paulo, ; Ribeirão Preto, Brazil
                [5 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, , University of São Paulo, ; Ribeirão Preto, Brazil
                [6 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, , University of São Paulo, ; Avenida do Café, s/n°, Ribeirão Preto, SP 14010-903 Brazil
                Article
                1224
                10.1186/s13287-019-1224-y
                6498654
                31046833
                fee1878e-7447-4e45-9ac3-48dcf8ed6124
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

                History
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: No. 2013/08135-2
                Funded by: FundRef http://dx.doi.org/10.13039/501100002322, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior;
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Molecular medicine
                mesenchymal stromal cells,priming,cell therapy,pro-inflammatory cytokines,pharmaceutical drugs,biomaterials,culture conditions

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