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      Effects of Freeze–Thawing and Intravenous Infusion on Mesenchymal Stromal Cell Gene Expression

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          Abstract

          Mesenchymal stromal cells (MSC) are increasingly used as an investigative therapeutic product for immune disorders and degenerative disease. Typically, MSC are isolated from human tissue, expanded in culture, and cryopreserved until usage. The safety and efficacy of MSC therapy will depend on the phenotypical and functional characteristics of MSC. The freeze-thawing procedure may change these characteristics. Furthermore, the cells encounter a microenvironment after administration that may impact their properties. It has been demonstrated that the majority of MSC localize to the lungs after intravenous infusion, making this the site to study the effects of the in vivo milieu on administered MSC. In this study, we investigated the effect of freeze-thawing and the mouse lung microenvironment on human adipose tissue-derived MSC. There were effects of freeze-thawing on the whole genome expression profile of MSC, although the effects did not exceed interdonor differences. There were no major changes in the expression of hemostatic regulators on transcriptional level, but significantly increased expression of procoagulant tissue factor on the surface of thawed adipose MSC, correlating with increased procoagulant activity of thawed cells. Exposure for 2 h to the lung microenvironment had a major effect on MSC gene expression and affected several immunological pathways. This indicates that MSC undergo functional changes shortly after infusion and this may influence the efficacy of MSC to modulate inflammatory responses. The results of this study demonstrate that MSC rapidly alter in response to the local milieu and disease-specific conditions may shape MSC after administration.

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          Most cited references14

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          Wnt signaling controls the fate of mesenchymal stem cells.

          Multipotential mesenchymal stem cells (MSCs) are able to differentiate along several known lineages and have been shown to be efficacious for in vivo wound repair. The growth and differentiation of MSCs are known to be tightly regulated via interactions with specific extracellular mediators. Recent studies have shown that Wnts and their downstream signaling pathways play an important role in the self-renewal and differentiation of MSCs. Indeed altered bone-mass is known to result from mutations in LRP5, a Wnt co-receptor, that suggests Wnt plays an important signaling role during bone formation, possibly involving MSCs. This review outlines the current understanding of the distinct Wnt intracellular pathways including both canonical beta-catenin/TCF(LEF1) signaling and non-canonical cascades mediated by JNK, PKC, Ca(2+) or Rho, and how they are involved in the regulation of MSC proliferation and differentiation. We also discuss the coordination between different Wnt signaling cascades to precisely control MSC cell fate decisions, and we dissect the functional cross-talk of Wnt signaling that is known to occur with other growth factor signaling pathways.
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            Therapeutic applications of mesenchymal stromal cells: paracrine effects and potential improvements.

            Among the various types of cell-to-cell signaling, paracrine signaling comprises those signals that are transmitted over short distances between different cell types. In the human body, secreted growth factors and cytokines instruct, among others, proliferation, differentiation, and migration. In the hematopoietic stem cell (HSC) niche, stromal cells provide instructive cues to stem cells via paracrine signaling and one of these cell types, known to secrete a broad panel of growth factors and cytokines, is mesenchymal stromal cells (MSCs). The factors secreted by MSCs have trophic, immunomodulatory, antiapoptotic, and proangiogenic properties, and their paracrine profile varies according to their initial activation by various stimuli. MSCs are currently studied as treatment for inflammatory diseases such as graft-versus-host disease and Crohn's disease, but also as treatment for myocardial infarct and solid organ transplantation. In addition, MSCs are investigated for their use in tissue engineering applications, in which their differentiation plays an important role, but as we have recently demonstrated, their trophic factors may also be involved. Furthermore, a functional improvement of MSCs might be obtained after preconditioning or tailoring the cells themselves. Also, the way the cells are clinically administered may be specialized for specific therapeutic scenarios. In this review we will first discuss the HSC niche, in which MSCs were recently identified and are thought to play an instructive and supportive role. We will then evaluate therapeutic applications that currently try to utilize the trophic and/or immunomodulatory properties of MSCs, and we will also discuss new options to enhance their therapeutic effects.
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              Familial Occurrence of Pulmonary Embolism after Intravenous, Adipose Tissue-Derived Stem Cell Therapy

              The therapeutic potential of human multipotent mesenchymal stromal cells, especially human adipose tissue-derived stem cells (hASC), is promising. However, there are concerns about the safety of infusion of hASC in human. Recently, we have experienced pulmonary embolism and infarct among family members who have taken multiple infusions of intravenous autologous hASC therapy. A 41-year-old man presented with chest pain for one month. Chest CT showed multiple pulmonary artery embolism and infarct at right lung. Serum D-dimer was 0.8 µg/mL (normal; 0-0.5 µg/mL). He had received intravenous autologous adipose tissue-derived stem cell therapy for cervical herniated intervertebral disc three times (one, two, and three months prior to the visit). His parents also received the same therapy five times and their chest CT also showed multiple pulmonary embolism. These cases represent artificial pulmonary embolisms and infarct after IV injection of hASC. Follow-up chest CT showed spontaneous resolution of lesions in all three patients.
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                Author and article information

                Journal
                Stem Cells and Development
                Stem Cells and Development
                Mary Ann Liebert Inc
                1547-3287
                1557-8534
                April 15 2016
                April 15 2016
                : 25
                : 8
                : 586-597
                Affiliations
                [1 ]Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
                [2 ]Center for Biomics, Erasmus Medical Center, Rotterdam, the Netherlands.
                [3 ]Department of Dermatology and Venerology, Lund University, Stockholm, Sweden.
                [4 ]Department of Nephrology and Intensive Care Medicine, Charité Universtätsmedizin Berlin, Berlin, Germany.
                [5 ]Berlin-Brandenburg Center/School for Regenerative Therapies (BCRT/BSRT), Charité Universtätsmedizin Berlin, Berlin, Germany.
                [6 ]Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden.
                Article
                10.1089/scd.2015.0329
                26914168
                0878e7a1-7df3-4ab6-a8d3-64cd666aea0b
                © 2016

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