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      The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine

      review-article
      *
      Journal of Cellular and Molecular Medicine
      Blackwell Publishing Ltd
      myofibroblast, fibrosis, cancer, tumour, stroma, ultrastructure, therapy

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          Abstract

          The phrase ‘translational research’conveys the idea of the pursuit of applications for the treatment of human disease.The myofibroblast, long known for having a role in wound-healing, and for its presence in fibrotic conditions and tumour stroma, is becoming a focus for translational research, not least through its increasingly documented role as a tumour-promoting cell.In fibroproliferative conditions, cancer and tissue engineering, the myofibroblast, derived partly and possibly from circulating bone-marrow-derived cells and epithelial-to-mesenchymal transformation, is attracting great attention.In cancer, this cell was initially regarded as a barrier to tumour dissemination, but there is now a growing body of evidence to indicate that it is an active participant in tumour progression.While the involvement of the myofibroblast in these pathological processes is pushing the myofibroblast into the limelight of translational medicine as a target for potential anti-fibrotic and anti-cancer therapy, there are still numerous indications from the literature that the myofibroblast is a poorly understood cell in terms of its differentiation.Partly, this is due to a failure to appreciate the contribution of electron microscopy to understanding the nature of this cell.This paper, therefore, is devoted to detailing the principal phenotypic characteristics of the myofibroblast and promotes the argument that understanding how the myofibroblast carries out its roles in normal biological and in pathological processes will be enhanced by a sound understanding of its cellular differentiation, which in turn arguably demands a significant ultrastructural input.

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          Most cited references110

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          The myofibroblast in wound healing and fibrocontractive diseases.

          G Gabbiani (2003)
          The demonstration that fibroblastic cells acquire contractile features during the healing of an open wound, thus modulating into myofibroblasts, has open a new perspective in the understanding of mechanisms leading to wound closure and fibrocontractive diseases. Myofibroblasts synthesize extracellular matrix components such as collagen types I and III and during normal wound healing disappear by apoptosis when epithelialization occurs. The transition from fibroblasts to myofibroblasts is influenced by mechanical stress, TGF-beta and cellular fibronectin (ED-A splice variant). These factors also play important roles in the development of fibrocontractive changes, such as those observed in liver cirrhosis, renal fibrosis, and stroma reaction to epithelial tumours. Copyright 2003 John Wiley & Sons, Ltd.
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            Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.

            The present study demonstrates that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in an in vitro coculture system. Human prostatic carcinoma-associated fibroblasts grown with initiated human prostatic epithelial cells dramatically stimulated growth and altered histology of the epithelial population. This effect was not detected when normal prostatic fibroblasts were grown with the initiated epithelial cells under the same experimental conditions. In contrast, carcinoma-associated fibroblasts did not affect growth of normal human prostatic epithelial cells under identical conditions. From these data, we conclude that in this human prostate cancer model, carcinoma-associated fibroblasts stimulate progression of tumorigenesis. Thus, carcinoma-associated fibroblasts can direct tumor progression of an initiated prostate epithelial cell.
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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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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                jcmm
                Journal of Cellular and Molecular Medicine
                Blackwell Publishing Ltd (Oxford, UK )
                1582-1838
                1582-4934
                January 2008
                25 December 2007
                : 12
                : 1
                : 22-37
                Affiliations
                Christie Hospital NHS Foundation Trust, Manchester, UK
                Author notes
                Correspondence to: Brian EYDEN, PhD, Department of Histopathology, Christie Hospital NHS Foundation Trust, Manchester M20 4BX, United Kingdom. Tel.: +44-161-446 3292 Fax : +44-161-446 3300 E-mail: brian.eyden@ 123456christie.nhs.uk
                Article
                10.1111/j.1582-4934.2007.00213.x
                3823470
                18182061
                8767c2fd-1268-4823-bce9-1c5520c86de9
                2008 Christie Hospital Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                History
                : 19 December 2007
                : 19 December 2007
                Categories
                Reviews

                Molecular medicine
                myofibroblast,fibrosis,cancer,tumour,stroma,ultrastructure,therapy
                Molecular medicine
                myofibroblast, fibrosis, cancer, tumour, stroma, ultrastructure, therapy

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