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      Macrophage-Associated Mesenchymal Stem Cells Assume an Activated, Migratory, Pro-Inflammatory Phenotype with Increased IL-6 and CXCL10 Secretion

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      Journal: PLoS ONE
      Publisher: Public Library of Science

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          Abstract

          Mesenchymal stem cells (MSCs) exhibit tropism for sites of tissue injury and tumors. However, the influence of the microenvironment on MSC phenotype and localization remains incompletely characterized. In this study, we begin to define a macrophage-induced MSC phenotype. These MSCs secrete interleukin-6 (IL-6), CCL5, and interferon gamma-induced protein-10 (CXCL10) and exhibit increased mobility in response to multiple soluble factors produced by macrophages including IL-8, CCL2, and CCL5. The pro-migratory phenotype is dependent on activation of a c-Jun N-terminal kinase (JNK) pathway. This work begins to identify the influence of macrophages on MSC biology. These interactions are likely to play an important role in the tissue inflammatory response and may provide insight into the migratory potential of MSCs in inflammation and tissue injury.

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          Adult mesenchymal stem cells for tissue engineering versus regenerative medicine.

          Arnold I. Caplan (2007)
          Adult mesenchymal stem cells (MSCs) can be isolated from bone marrow or marrow aspirates and because they are culture-dish adherent, they can be expanded in culture while maintaining their multipotency. The MSCs have been used in preclinical models for tissue engineering of bone, cartilage, muscle, marrow stroma, tendon, fat, and other connective tissues. These tissue-engineered materials show considerable promise for use in rebuilding damaged or diseased mesenchymal tissues. Unanticipated is the realization that the MSCs secrete a large spectrum of bioactive molecules. These molecules are immunosuppressive, especially for T-cells and, thus, allogeneic MSCs can be considered for therapeutic use. In this context, the secreted bioactive molecules provide a regenerative microenvironment for a variety of injured adult tissues to limit the area of damage and to mount a self-regulated regenerative response. This regenerative microenvironment is referred to as trophic activity and, therefore, MSCs appear to be valuable mediators for tissue repair and regeneration. The natural titers of MSCs that are drawn to sites of tissue injury can be augmented by allogeneic MSCs delivered via the bloodstream. Indeed, human clinical trials are now under way to use allogeneic MSCs for treatment of myocardial infarcts, graft-versus-host disease, Crohn's Disease, cartilage and meniscus repair, stroke, and spinal cord injury. This review summarizes the biological basis for the in vivo functioning of MSCs through development and aging.
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            Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages.

            Jaehyup Kim, Peiman Hematti (2009)
            Mesenchymal stem cells (MSCs) are capable of modulating the immune system through interaction with a wide range of immune cells. This study investigates the hypothesis that interaction of MSCs with macrophages could play a significant role in their antiinflammatory/immune modulatory effects. MSCs were derived from bone marrow and monocytes were isolated from peripheral blood of healthy donors. We cultured human monocytes for 7 days without any added cytokines to generate macrophages, and then cocultured them for 3 more days with culture-expanded MSCs. We used cell surface antigen expression and intracellular cytokine expression patterns to study the immunophenotype of macrophages at the end of this coculture period, and phagocytic assays to investigate their functional activity in vitro. Macrophages cocultured with MSCs consistently showed high-level expression of CD206, a marker of alternatively activated macrophages. Furthermore, these macrophages expressed high levels of interleukin (IL)-10 and low levels of IL-12, as determined by intracellular staining, typical of alternatively activated macrophages. However, macrophages cocultured with MSCs also expressed high levels of IL-6 and low levels of tumor necrosis factor-alpha (TNF-alpha) compared to controls. Functionally, macrophages cocultured with MSCs showed a higher level of phagocytic activity. We describe a novel type of human macrophage generated in vitro after coculture with MSCs that assumes an immunophenotype defined as IL-10-high, IL-12-low, IL-6-high, and TNF-alpha-low secreting cells. These MSC-educated macrophages may be a unique and novel type of alternatively activated macrophage with a potentially significant role in tissue repair.
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              Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas.

              Akira Nakamizo, Frank Marini, Toshiyuki Amano … (2005)
              The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 4 April 2012
                Volume: 7
                Issue: 4
                Electronic Location Identifier: e35036
                Affiliations
                [1 ]Department of Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, United States of America
                [2 ]Department of Medicine, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, United States of America
                [3 ]Department of Pediatrics, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, United State of America
                University of Sao Paulo – USP, Brazil
                Author notes

                Conceived and designed the experiments: KA DB JG. Performed the experiments: KA. Analyzed the data: KA JG. Contributed reagents/materials/analysis tools: JG DB. Wrote the paper: KA DB JG.

                Article
                Publisher ID: PONE-D-11-22035
                DOI: 10.1371/journal.pone.0035036
                PMC ID: 3319627
                PubMed ID: 22496888
                SO-VID: e99a4fdb-fb03-4833-8b07-7e67ac18caf5
                Copyright © Anton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 4 November 2011
                Date accepted : 8 March 2012
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Immune Physiology
                Subject: Immune Cells
                Subject: Immunology
                Subject: Immunopathology
                Subject: Molecular Cell Biology
                Subject: Cellular Types
                Subject: Stem Cells
                Subject: Adult Stem Cells
                Subject: Mesenchymal Stem Cells
                Subject: Blood Cells
                Subject: Medicine
                Subject: Clinical Immunology
                Subject: Immune System
                Subject: Cytokines
                Subject: Immunity
                Subject: Inflammation

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                ScienceOpen disciplines: Uncategorized

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