Serini G, Gabbiani GMechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 250:273-283

University of Geneva, Genève, Geneva, Switzerland
Experimental Cell Research (Impact Factor: 3.25). 09/1999; 250(2):273-83. DOI: 10.1006/excr.1999.4543
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Available from: Guido Serini, Sep 19, 2015
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    • "For instance, loss of TGFβ signaling in fibroblasts causes intraepithelial neoplasia, suggesting that TGFβ controls the activity of fibroblasts as well as the oncogenic potential of neighboring epithelial cells (Bhowmick et al. 2004). Experimental regeneration models such as partial hepatectomy indicate a role for TGFβ only at late stage of wound healing, mainly for restoration of ECM and new vessel formation (Serini and Gabbiani 1999). The pleiotropic effects of TGFβ upon different cell types (hepatocytes and HSCs) and the time of action during liver damaging conditions remain yet unclear. "
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    ABSTRACT: Liver exhibits a remarkable maintenance of functional homeostasis in the presence of a variety of damaging toxic factors. Tissue regeneration involves cell replenishment and extracellular matrix remodeling. Key regulator of homeostasis is the transforming growth factor-β (TGFβ) cytokine. To understand the role of TGFβ during liver regeneration, we used the single-dose carbon tetrachloride (CCl4) treatment in mice as a model of acute liver damage. We combined this with in vivo inhibition of the TGFβ pathway by a small molecule inhibitor, LY364947, which targets the TGFβ type I receptor kinase [activin receptor-like kinase 5 (ALK5)] in hepatocytes but not in activated stellate cells. Co-administration of LY364947 inhibitor and CCl4 toxic agent resulted in enhanced liver regeneration; cell proliferation (measured by PCNA, phosphorylated histone 3, p21) levels were increased in CCl4 + LY364947 versus CCl4-treated mice. Recovery of CCl4-metabolizing enzyme CYP2E1 expression in hepatocytes is enhanced 7 days after CCl4 intoxication in the mice that received also the TGFβ inhibitor. In summary, a small molecule inhibitor that blocks ALK5 downstream signaling and halts the cytostatic role of TGFβ pathway results in increased cell regeneration and improved liver function during acute liver damage. Thus, in vivo ALK5 modulation offers insight into the role of TGFβ, not only in matrix remodeling and fibrosis, but also in cell regeneration.
    Archive für Toxikologie 01/2015; DOI:10.1007/s00204-014-1436-y · 5.98 Impact Factor
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    • "In other words, cancer cells are dynamically altered (i.e. their genetic background is constantly changing), which allows them to secrete a diverse repertoire of growth factors and paracrine signaling molecules, which, in turn, are able to shape the tumor microenvironment in their favor and address any new challenges encountered in the metastatic cascade (Elenbaas and Weinberg, 2001; Serini and Gabbiani, 1999). We have previously proposed a model of CAF-directed metastatic progression, according to which CAFs are able to migrate within the tumor microenvironment and the tumor compartment in a cohort configuration by developing a specific migratory, adhesive and paracrine signaling machinery (Karagiannis et al., 2013, 2012b). "
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    ABSTRACT: It has been suggested that cancer-associated fibroblasts (CAFs) positioned at the desmoplastic areas of various types of cancer are capable of executing a migratory program, characterized by accelerated motility and collective configuration. Since CAFs are reprogrammed derivatives of normal progenitors, including quiescent fibroblasts, we hypothesized that such migratory program could be context-dependent, thus being regulated by specific paracrine signals from the adjacent cancer population. Using the traditional scratch assay setup, we showed that only specific colon cancer cell lines (i.e. HT29) were able to induce collective CAF migration. By performing quantitative proteomics (SILAC), we identified a 2.7-fold increase of claudin-11, a member of the tight junction apparatus, in CAFs that exerted such collectivity in their migratory pattern. Further proteomic investigations of cancer cell line secretomes revealed a specific signature, involving TGF-β, as potential mediator of this effect. Normal colonic fibroblasts stimulated with TGF-β exerted myofibroblastic differentiation, occludin (OCLN) and claudin-11 (CLDN11) overexpression and cohort formation. Subsequently, inhibition of TGF-β attenuated all the previous effects. Immunohistochemistry of the universal tight junction marker occludin in a cohort of 30 colorectal adenocarcinoma patients defined a CAF subpopulation expressing tight junctions. Overall, these data suggest that cancer cells may induce CLDN11 overexpression and subsequent collective migration of peritumoral CAFs via TGF-β secretion.
    Molecular oncology 11/2013; 8(2). DOI:10.1016/j.molonc.2013.10.008 · 5.33 Impact Factor
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    • "contrast, cells cultured on aECM with adsorbed TGFb 1 show less pronounced collagen I expression on all aECMs (Fig. 2B). Moreover, MFb can be characterized by the expression of ED-A FN, a specific splice variant of fibronectin [6] [40], which is also important in promoting further MFb differentiation [39]. As for the other TGFb 1 -regulated MFb marker genes, we found down-regulation of the ED-A FN mRNA level after 72 h for dFb grown on coll/ hsHA in unstimulated (Fig. 3A, white bars) or TGFb 1 -stimulated (Fig. 3A, grey and black bars) samples in comparison with dFb grown on coll and coll/HA. "
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    ABSTRACT: Sulfated glycosaminoglycans are promising components for functional biomaterials since sulfate groups modulate the binding of growth factors and thereby influence wound healing. Here, we have investigated the influence of an artificial extracellular matrix (aECM) consisting of collagen I (coll) and hyaluronan (HA) or highly sulfated HA (hsHA) on dermal fibroblasts (dFb) with respect to their differentiation into myofibroblasts (MFb). Fibroblasts were cultured on aECM in the presence of aECM-adsorbed or soluble transforming growth factor β1 (TGFβ1). The synthesis of α-smooth muscle actin (αSMA), collagen and the ED-A splice variant of fibronectin (ED-A FN) were analyzed at the mRNA and protein levels. Furthermore, we investigated the bioactivity and signal transduction of TGFβ1 in the presence of aECM and finally made interaction studies of soluble HA or hsHA with TGFβ1. Artificial ECM composed of coll and hsHA prevents TGFβ1-stimulated αSMA, collagen and ED-A FN expression. Our data suggest an impaired TGFβ1 bioactivity and downstream signaling in the presence of aECM containing hsHA, shown by massively reduced Smad2/3 translocation to the nucleus. These data are explained by in silico docking experiments demonstrating the occupation of the TGFβ-receptor I binding site by hsHA. Possibly, HA sulfation has a strong impact on TGFβ1-driven differentiation of dFb and thus could be used to modulate the properties of biomaterials.
    Acta biomaterialia 08/2013; 9(8):7775–7786. DOI:10.1016/j.actbio.2013.04.023 · 6.03 Impact Factor
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