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      Characterization of the Conditioned Medium from Amniotic Membrane Cells: Prostaglandins as Key Effectors of Its Immunomodulatory Activity

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          Abstract

          We previously demonstrated that cells isolated from the mesenchymal region of the human amniotic membrane (human amniotic mesenchymal tissue cells, hAMTC) possess immunoregulatory roles, such as inhibition of lymphocyte proliferation and cytokine production, and suppression of generation and maturation of monocyte-derived dendritic cells, as reported for MSC from other sources. The precise factors and mechanisms responsible for the immunoregulatory roles of hAMTC remain unknown. In this study, we aimed to identify the soluble factors released by hAMTC and responsible for the anti-proliferative effect on lymphocytes, and the mechanisms underlying their actions, in vitro. Conditioned medium (CM) was prepared under routine culture conditions from hAMTC (CM-hAMTC) and also from fragments of the whole human amniotic membrane (CM-hAM). We analyzed the thermostability, chemical nature, and the molecular weight of the factors likely responsible for the anti-proliferative effects. We also evaluated the participation of cytokines known to be involved in the immunomodulatory actions of MSC from other sources, and attempted to block different synthetic pathways. We demonstrate that the inhibitory factors are temperature-stable, have a small molecular weight, and are likely of a non-proteinaceous nature. Only inhibition of cyclooxygenase pathway partially reverted the anti-proliferative effect, suggesting prostaglandins as key effector molecules. Factors previously documented to take part in the inhibitory effects of MSCs from other sources (HGF, TGF-β, NO and IDO) were not involved. Furthermore, we prove for the first time that the anti-proliferative effect is intrinsic to the amniotic membrane and cells derived thereof, since it is manifested in the absence of stimulating culture conditions, as opposed to MSC derived from the bone marrow, which possess an anti-proliferative ability only when cultured in the presence of activating stimuli. Finally, we show that the amniotic membrane could be an interesting source of soluble factors, without referring to extensive cell preparation.

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          IDO expression by dendritic cells: tolerance and tryptophan catabolism.

          Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.
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            Adult mesenchymal stem cells for tissue engineering versus regenerative medicine.

            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 cells in the Wharton's jelly of the human umbilical cord.

              The Wharton's jelly of the umbilical cord contains mucoid connective tissue and fibroblast-like cells. Using flow cytometric analysis, we found that mesenchymal cells isolated from the umbilical cord express matrix receptors (CD44, CD105) and integrin markers (CD29, CD51) but not hematopoietic lineage markers (CD34, CD45). Interestingly, these cells also express significant amounts of mesenchymal stem cell markers (SH2, SH3). We therefore investigated the potential of these cells to differentiate into cardiomyocytes by treating them with 5-azacytidine or by culturing them in cardiomyocyte-conditioned medium and found that both sets of conditions resulted in the expression of cardiomyocyte markers, namely N-cadherin and cardiac troponin I. We also showed that these cells have multilineage potential and that, under suitable culture conditions, are able to differentiate into cells of the adipogenic and osteogenic lineages. These findings may have a significant impact on studies of early human cardiac differentiation, functional genomics, pharmacological testing, cell therapy, and tissue engineering by helping to eliminate worrying ethical and technical issues.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                10 October 2012
                : 7
                : 10
                : e46956
                Affiliations
                [1 ]Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italia
                [2 ]Doctoral School of Molecular Medicine, University of Milan, Milano, Italia
                [3 ]Institute of Cell Biology, Histology and Embryology, Center for Molecular Medicine, Medical University of Graz, Graz, Austria
                University of Pittsburgh, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DR SP OP. Performed the experiments: DR SP MM. Analyzed the data: DR SP OP. Contributed reagents/materials/analysis tools: PS. Wrote the paper: DR SP OP.

                Article
                PONE-D-12-10230
                10.1371/journal.pone.0046956
                3468614
                23071674
                660eb548-36f6-4458-9bcf-543c04b3d751
                Copyright @ 2012

                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
                : 12 April 2012
                : 6 September 2012
                Page count
                Pages: 14
                Funding
                This study was supported in part by Fondazione della Comunità Bresciana ONLUS (Fondo per una Scienza Etica), Ministero dell’Istruzione, dell’Università e della Ricerca - MIUR (FIRB RBNE06JBCW_002), Fondazione Cariplo (grant n° 211-0495), and Fondazione Poliambulanza. These funding bodies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Cell Physiology
                Immunology
                Immunity
                Immunoregulation
                Immunomodulation
                Molecular Cell Biology
                Cellular Types
                Stem Cells
                Adult Stem Cells
                Mesenchymal Stem Cells
                Signal Transduction
                Signaling in Cellular Processes

                Uncategorized
                Uncategorized

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