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      The role of non-hematopoietic stromal cells in the persistence of inflammation

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          Inflammation results from the complex interaction between hematopoietic and stromal cells and growing evidence supports a key role for the stroma in driving the switch from acute resolving to persistence in chronic inflammatory diseases. Stromal cells have also been shown to play a critical role in cancer biology, being involved in cancer growth, dissemination, and inhibition of the autologous immune response, ultimately favoring persistence and metastatic spread. Similarly, blood and lymphatic endothelial cells contribute to tissue homeostasis during physiological inflammation but also lead to discorded leukocyte and tumor cell accumulation in pathological inflammation and cancer. This review aims to summarize the role that pathogenic stroma plays in the pathogenesis of diseases such as cancer and chronic inflammation.

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          Most cited references 93

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          Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.

          The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
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            Evidence that fibroblasts derive from epithelium during tissue fibrosis.

            Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1(+), CD34(-) fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1(+) fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.
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              Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.

              Fibrocytes are a distinct population of blood-borne cells that display a unique cell surface phenotype (collagen I+/CD11b+/CD13+/CD34+/CD45RO+/MHC class II+/CD86+) and exhibit potent immunostimulatory activities. Circulating fibrocytes rapidly enter sites of tissue injury, suggesting an important role for these cells in wound repair. However, the regulatory processes that govern the differentiation of blood-borne fibrocytes and the mechanisms that underlie the migration of these cells to wound sites are currently not known. We report herein that ex vivo cultured fibrocytes can differentiate from a CD14+-enriched mononuclear cell population and that this process requires contact with T cells. Furthermore, we demonstrate that TGF-beta1 (1-10 ng/ml), an important fibrogenic and growth-regulating cytokine involved in wound healing, increases the differentiation and functional activity of cultured fibrocytes. Because fibrocytes home to sites of tissue injury, we examined the role of chemokine/chemokine receptor interactions in fibrocyte trafficking. We show that secondary lymphoid chemokine, a ligand of the CCR7 chemokine receptor, acts as a potent stimulus for fibrocyte chemotaxis in vitro and for the homing of injected fibrocytes to sites of cutaneous tissue injury in vivo. Finally, we demonstrate that differentiated, cultured fibrocytes express alpha smooth muscle actin and contract collagen gels in vitro, two characteristic features of wound-healing myofibroblasts. These data provide important insight into the control of fibrocyte differentiation and trafficking during tissue repair and significantly expand their potential role during wound healing.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immun.
                Frontiers in Immunology
                Frontiers Media S.A.
                14 January 2013
                : 3
                Centre for Translational Inflammation Research, Arthritis Research UK, Rheumatology Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, UK
                Author notes

                Edited by: Mark C. Coles, University of York, UK

                Reviewed by: Masaaki Murakami, Osaka University, Japan; Nancy Ruddle, Yale University School of Medicine, USA

                *Correspondence: Francesca Barone and Chris D. Buckley, Centre for Translational Inflammation Research, Arthritis Research UK, Rheumatology Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham B15 2WD, UK. e-mail: f.barone@ 123456bham.ac.uk ; c.d.buckley@ 123456bham.ac.uk

                This article was submitted to Frontiers in Antigen Presenting Cell Biology, a specialty of Frontiers in Immunology.

                Copyright © Barone, Nayar and Buckley.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

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                Figures: 0, Tables: 1, Equations: 0, References: 121, Pages: 7, Words: 0
                Review Article


                rheumatoid arthritis, ectopic lymphoneogenesis, endothelium, fibroblasts, lymphatics


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