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dc.contributor.authorStrippoli, Raffaele 
dc.contributor.authorSandoval, Pilar
dc.contributor.authorMoreno-Vicente, Roberto 
dc.contributor.authorRossi, Lucia
dc.contributor.authorBattistelli, Cecilia
dc.contributor.authorTerri, Michela
dc.contributor.authorPascual-Antón, Lucía
dc.contributor.authorLoureiro, Marta 
dc.contributor.authorMatteini, Francesca
dc.contributor.authorCalvo, Enrique 
dc.contributor.authorJiménez-Heffernan, José Antonio
dc.contributor.authorGomez, Manuel J 
dc.contributor.authorJimenez-Jimenez, Victor 
dc.contributor.authorSanchez-Cabo, Fatima 
dc.contributor.authorVazquez, Jesus 
dc.contributor.authorTripodi, Marco
dc.contributor.authorLópez-Cabrera, Manuel
dc.contributor.authordel Pozo, Miguel Angel 
dc.date.accessioned2020-09-22T07:10:35Z
dc.date.available2020-09-22T07:10:35Z
dc.date.issued2020-08
dc.identifier.citationCell Death Dis. 2020; 11(8):647es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/11057
dc.description.abstractDespite their emerging relevance to fully understand disease pathogenesis, we have as yet a poor understanding as to how biomechanical signals are integrated with specific biochemical pathways to determine cell behaviour. Mesothelial-to-mesenchymal transition (MMT) markers colocalized with TGF-β1-dependent signaling and yes-associated protein (YAP) activation across biopsies from different pathologies exhibiting peritoneal fibrosis, supporting mechanotransduction as a central driving component of these class of fibrotic lesions and its crosstalk with specific signaling pathways. Transcriptome and proteome profiling of the response of mesothelial cells (MCs) to linear cyclic stretch revealed molecular changes compatible with bona fide MMT, which (i) overlapped with established YAP target gene subsets, and were largely dependent on endogenous TGF-β1 signaling. Importantly, TGF-β1 blockade blunts the transcriptional upregulation of these gene signatures, but not the mechanical activation and nuclear translocation of YAP per se. We studied the role therein of caveolin-1 (CAV1), a plasma membrane mechanotransducer. Exposure of CAV1-deficient MCs to cyclic stretch led to a robust upregulation of MMT-related gene programs, which was blunted upon TGF-β1 inhibition. Conversely, CAV1 depletion enhanced both TGF-β1 and TGFBRI expression, whereas its re-expression blunted mechanical stretching-induced MMT. CAV1 genetic deficiency exacerbated MMT and adhesion formation in an experimental murine model of peritoneal ischaemic buttons. Taken together, these results support that CAV1-YAP/TAZ fine-tune the fibrotic response through the modulation of MMT, onto which TGF-β1-dependent signaling coordinately converges. Our findings reveal a cooperation between biomechanical and biochemical signals in the triggering of MMT, representing a novel potential opportunity to intervene mechanically induced disorders coursing with peritoneal fibrosis, such as post-surgical adhesions.es_ES
dc.description.sponsorshipThis work was supported by grants from: MICINN and MINECO (SAF2014-51876-R and SAF2017-83130-R; MINSEV1512-07-2016; CSD2009-0016 and BFU2016-81912-REDC), Fundació La Marató de TV3 (674/C/2013), Worldwide Cancer Research16–0404, BIOPOL, 641639, Tec4Bio consortium; P2018/NMT4443) (all to M.A.d.P.); (MINECO/FEDER) (SAF2016-80648-R) and Marie Sklodowska-Curie Innovative Training Networks-European Training Networks (812699) both to MLC; by an AIRC grant (IG 18843); and from Sapienza University of Rome (RM116154BE5E14B2) (all to M.T.). R.M-V. was supported by an FPI predoctoral fellowship from MICINN (BES-2012-052980; SAF2011-25047). L.P.-A. was supported by a predoctoral fellowship from MICINN (BES-2017-080416; SAF2016-80648-R). V.J-J. was ECR trainee of MSCA-ITN (BIOPOL, 641639). The CNIC is supported by the ISCIII, the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).es_ES
dc.language.isoenges_ES
dc.publisherSpringer Nature [academic journals on nature.com]es_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleCaveolin1 and YAP drive mechanically induced mesothelial to mesenchymal transition and fibrosis.es_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID32811813es_ES
dc.format.volume11es_ES
dc.format.number8es_ES
dc.format.page647es_ES
dc.identifier.doi10.1038/s41419-020-02822-1es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderMinisterio de Ciencia e Innovación (España)es_ES
dc.contributor.funderFundació La Maratóes_ES
dc.contributor.funderWorldwide Cancer Researches_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.contributor.funderSapineza University of Romees_ES
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderFundación ProCNICes_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn2041-4889es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41419-020-02822-1es_ES
dc.identifier.journalCell death & diseasees_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Señalización por Integrinases_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Proteómica cardiovasculares_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Proteómica / Metabolómicaes_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformáticaes_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2014-51876-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2017-83130-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/MINSEV1512-07-2016es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/CSD2009-0016es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2016-81912-REDCes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BES-2012-052980es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2011-25047es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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