title: Physiological Fluid Flow Moderates Fibroblast Responses to TGF-β1.
abstract: Fibroblasts are the major cellular component of connective tissue and experience mechanical perturbations due to matrix remodelling and interstitial fluid movement. Transforming growth factor β1 (TGF-β1) can promote differentiation of fibroblasts in vitro to a contractile myofibroblastic phenotype characterised by the presence of α-smooth muscle actin (α-SMA) rich stress fibres. To study the role of mechanical stimulation in this process, we examined the response of primary human fibroblasts to physiological levels of fluid movement and its influence on fibroblast differentiation and responses to TGF-β1. We reported that in both oral and dermal fibroblasts, physiological levels of fluid flow induced widespread changes in gene expression compared to static cultures, including up-regulation of genes associated with TGFβ signalling and endocytosis. TGF-β1, activin A and markers of myofibroblast differentiation including α-SMA and collagen IA1 were also increased by flow but surprisingly the combination of flow and exogenous TGF-β1 resulted in reduced differentiation. Our findings suggest this may result from enhanced internalisation of caveolin and TGF-β receptor II. These findings suggest that a) low levels of fluid flow induce myofibroblast differentiation and b) fluid flow antagonises the fibroblast response to pro-differentiation signals such as TGF-β1. We propose that this may be a novel mechanism by which mechanical forces buffer responses to chemical signals in vivo, maintaining a context-specific fibroblast phenotype. J. Cell. Biochem. 118: 878-890, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Academic Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, UK.
authors.forename: Sadhvi
authors.initials: S
authors.lastname: Nithiananthan
authors.affiliation: Academic Unit of Restorative Dentistry, School of Clinical Dentistry, University of Sheffield, Sheffield, UK.
authors.forename: Aileen
authors.initials: A
authors.lastname: Crawford
authors.affiliation: Department of Neuroscience, Academic Neurology Unit, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Johnathan Cooper
authors.initials: JC
authors.lastname: Knock
authors.affiliation: Academic Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, UK.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lambert
authors.affiliation: Academic Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Whawell
mesh_terms: D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D028341:Activins / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D057446:Hydrodynamics; D009055:Mouth / Q000166:cytology / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C495540:CAV1 protein, human; D051242:Caveolin 1; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C422405:activin A; D028341:Activins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: ACTIVIN A; CAVEOLIN; FLUID FLOW; FOLLISTATIN; TGF-β1; α-SMA