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dc.contributor.authorBagchi, Rushita A
dc.contributor.authorRoche, Patricia
dc.contributor.authorAroutiounova, Nina
dc.contributor.authorEspira, Leon
dc.contributor.authorAbrenica, Bernard
dc.contributor.authorSchweitzer, Ronen
dc.contributor.authorCzubryt, Michael P
dc.date.accessioned2016-04-14T16:09:44Z
dc.date.available2016-04-14T16:09:44Z
dc.date.issued2016-03-17
dc.identifier.urihttp://hdl.handle.net/1993/31223
dc.description.abstractBackground: Resident fibroblasts synthesize the cardiac extracellular matrix, and can undergo phenotype conversion to myofibroblasts to augment matrix production, impairing function and contributing to organ failure. A significant gap in our understanding of the transcriptional regulation of these processes exists. Given the key role of this phenotype conversion in fibrotic disease, the identification of such novel transcriptional regulators may yield new targets for therapies for fibrosis. Results: Using explanted primary cardiac fibroblasts in gain- and loss-of-function studies, we found that scleraxis critically controls cardiac fibroblast/myofibroblast phenotype by direct transcriptional regulation of myriad genes that effectively define these cells, including extracellular matrix components and α-smooth muscle actin. Scleraxis furthermore potentiated the TGFβ/Smad3 signaling pathway, a key regulator of myofibroblast conversion, by facilitating transcription complex formation. While scleraxis promoted fibroblast to myofibroblast conversion, loss of scleraxis attenuated myofibroblast function and gene expression. These results were confirmed in scleraxis knockout mice, which were cardiac matrix-deficient and lost ~50 % of their complement of cardiac fibroblasts, with evidence of impaired epithelial-to-mesenchymal transition (EMT). Scleraxis directly transactivated several EMT marker genes, and was sufficient to induce mesenchymal/fibroblast phenotype conversion of A549 epithelial cells. Conversely, loss of scleraxis attenuated TGFβ-induced EMT marker expression. Conclusions: Our results demonstrate that scleraxis is a novel and potent regulator of cellular progression along the continuum culminating in the cardiac myofibroblast phenotype. Scleraxis was both sufficient to drive conversion, and required for full conversion to occur. Scleraxis fulfills this role by direct transcriptional regulation of key target genes, and by facilitating TGFβ/Smad signaling. Given the key role of fibroblast to myofibroblast conversion in fibrotic diseases in the heart and other tissue types, scleraxis may be an important target for therapeutic development.en_US
dc.description.sponsorshipCanadian Institutes of Health Research grant MOP-106671 (MPC); St. Boniface Hospital Foundation; CIHR Doctoral research award (RAB); Research Manitoba studentship (PR).en_US
dc.language.isoengen_US
dc.publisherBMC Biologyen_US
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectFibroblasten_US
dc.subjectMyofibroblasten_US
dc.subjectTranscriptionen_US
dc.subjectGene expressionen_US
dc.subjectPhenoconversionen_US
dc.subjectExtracellular matrixen_US
dc.subjectEMTen_US
dc.titleThe transcription factor scleraxis is a critical regulator of cardiac fibroblast phenotypeen_US
dc.typeArticleen_US
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1186/s12915-016-0243-8


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