2026-06-14T03:40:07Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/110572024-10-31T11:41:36Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Strippoli, Raffaele
author
Sandoval, Pilar
author
Moreno-Vicente, Roberto
author
Rossi, Lucia
author
Battistelli, Cecilia
author
Terri, Michela
author
Pascual-Antón, Lucía
author
Loureiro, Marta
author
Matteini, Francesca
author
Calvo, Enrique
author
Jiménez-Heffernan, José Antonio
author
Gomez, Manuel J
author
Jimenez-Jimenez, Victor
author
Sanchez-Cabo, Fatima
author
Vazquez, Jesus
author
Tripodi, Marco
author
López-Cabrera, Manuel
author
del Pozo, Miguel Angel
funder
Ministerio de Economía y Competitividad (España)
funder
Ministerio de Ciencia e Innovación (España)
funder
Fundación La Marató TV3
funder
Worldwide Cancer Research
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Sapienza University of Rome (Italia)
funder
Instituto de Salud Carlos III
funder
Fundación ProCNIC
2020-09-22T07:10:35Z
2020-09-22T07:10:35Z
2020-08
Cell Death Dis. 2020; 11(8):647
10.1038/s41419-020-02822-1
2041-4889
Cell death & disease
32811813
http://hdl.handle.net/20.500.12105/11057
Despite 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.
eng
Caveolin1 and YAP drive mechanically induced mesothelial to mesenchymal transition and fibrosis.
journal article
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
URL
https://repisalud.isciii.es/bitstreams/b7e6311b-aedc-4bf4-9676-4a0b9b0d6af8/download
File
MD5
d88d9d2425a8db054e895d7dfa22e7e9
15049187
application/pdf
Caveolin1AndYAPDriveMechanically_2020.pdf
URL
https://repisalud.isciii.es/bitstreams/3327bcfc-7806-4bc6-86ad-ba5ba7e2755e/download
File
MD5
1a5169e27eb104b89ce05fcfe06c590e
292745
application/pdf
Caveolin1AndYAPDriveMechanically_2020_MOESM1_ESM.pdf
URL
https://repisalud.isciii.es/bitstreams/d05eaf88-46da-4d44-ac46-95c4b3ab1f74/download
File
MD5
c44be0cf4c510d54f19b6fbeeca389fe
1443896
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM2_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/549f5e0b-0df2-4633-9658-d8de290fab10/download
File
MD5
544905ed24220d9e9242b1df16486137
1718912
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM3_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/38baf7e3-033e-4268-b029-83e86bfd0577/download
File
MD5
d622646b5d12efbc656043a0e39fd2b2
4837004
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM4_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/49799f9e-afb2-4272-9622-e56fca0231f5/download
File
MD5
d622646b5d12efbc656043a0e39fd2b2
4837004
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM4_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/c50f66df-d881-414f-8137-17ab50a55fac/download
File
MD5
00a3be66a4b247002898750c63053401
3395568
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM5_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/7f9744cc-8c50-44ec-87b8-7f4006348580/download
File
MD5
36272e2083fb5df9db1d56e4525605c3
757456
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM6_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/0c52219c-da1e-49d4-bd33-f58c6801d7e7/download
File
MD5
e49295299ad8304bfe2bccb017263f27
775304
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM7_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/6ec4718c-e79b-4458-b3d5-c991523b9618/download
File
MD5
3df3616d2f11376ad88e35feea480584
835204
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM8_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/1abe46de-5e36-4dbf-9e3c-407217d1aa79/download
File
MD5
fd94ca3dd36adf8b872da12e8e88e6ce
782164
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM9_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/0cb03938-f8c3-40e0-b65b-c1e7aa0b9b80/download
File
MD5
bc1ef3eddba8ec7b826cd7476aea0c99
631168
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM10_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/ae7b1f27-d613-470a-89e6-ff94fb9237c9/download
File
MD5
55d7cad2d7400793653247f8e579ef79
931492
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM11_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/896d8214-c281-4d58-a300-4f76fe4fea02/download
File
MD5
d4f014f173652cf1919b7d10b323a5f5
3086318
image/tiff
Caveolin1AndYAPDriveMechanically_2020_MOESM12_ESM.tif
URL
https://repisalud.isciii.es/bitstreams/31d1840e-5623-49ed-9cc2-791394bbbfd0/download
File
MD5
652aeeed8bf634ebb045cbd8bdecb3c0
77400
text/plain
Caveolin1AndYAPDriveMechanically_2020.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/46866910-be60-4e36-bdd1-c0b536ec5bdd/download
File
MD5
feb957717eee43c7608ec4ad31ef9d36
5243
text/plain
Caveolin1AndYAPDriveMechanically_2020_MOESM1_ESM.pdf.txt