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dc.contributor.author
Kollmannsberger, Philip
dc.contributor.author
Bidan, Cécile M.
dc.contributor.author
Dunlop, John W.C.
dc.contributor.author
Fratzl, Peter
dc.contributor.author
Vogel, Viola
dc.date.accessioned
2018-05-28T11:55:48Z
dc.date.available
2018-05-28T11:55:48Z
dc.date.issued
2018-01
dc.identifier.other
10.1126/sciadv.aao4881
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/266235
dc.identifier.doi
10.3929/ethz-b-000232359
dc.description.abstract
Myofibroblasts orchestrate wound healing processes, and if they remain activated, they drive disease progression such as fibrosis and cancer. Besides growth factor signaling, the local extracellular matrix (ECM) and its mechanical properties are central regulators of these processes. It remains unknown whether transforming growth factor–β (TGF-β) and tensile forces work synergistically in up-regulating the transition of fibroblasts into myofibroblasts and whether myofibroblasts undergo apoptosis or become deactivated by other means once tissue homeostasis is reached. We used three-dimensional microtissues grown in vitro from fibroblasts in macroscopically engineered clefts for several weeks and found that fibroblasts transitioned into myofibroblasts at the highly tensed growth front as the microtissue progressively closed the cleft, in analogy to closing a wound site. Proliferation was up-regulated at the growth front, and new highly stretched fibronectin fibers were deposited, as revealed by fibronectin fluorescence resonance energy transfer probes. As the tissue was growing, the ECM underneath matured into a collagen-rich tissue containing mostly fibroblasts instead of myofibroblasts, and the fibronectin fibers were under reduced tension. This correlated with a progressive rounding of cells from the growth front inward, with decreased α–smooth muscle actin expression, YAP nuclear translocation, and cell proliferation. Together, this suggests that the myofibroblast phenotype is stabilized at the growth front by tensile forces, even in the absence of endogenously supplemented TGF-β, and reverts into a quiescent fibroblast phenotype already 10 μm behind the growth front, thus giving rise to a myofibroblast-to-fibroblast transition. This is the hallmark of reaching prohealing homeostasis.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
American Association for the Advancement of Science (AAAS)
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc/4.0/
dc.title
Tensile forces drive a reversible fibroblast-to-myofibroblast transition during tissue growth in engineered clefts
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial 4.0 International
ethz.journal.title
Science Advances
ethz.journal.volume
4
en_US
ethz.journal.issue
1
en_US
ethz.pages.start
eaao4881
en_US
ethz.size
10 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
How mechanical forces regulate multicellular growth in defined 3D geometries
en_US
ethz.identifier.scopus
ethz.publication.place
Washington, DC
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02540 - Institut für Translationale Medizin / Institute of Translational Medicine::03640 - Vogel, Viola / Vogel, Viola
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02540 - Institut für Translationale Medizin / Institute of Translational Medicine::03640 - Vogel, Viola / Vogel, Viola
en_US
ethz.grant.agreementno
327065
ethz.grant.fundername
EC
ethz.grant.funderDoi
10.13039/501100000780
ethz.grant.program
FP7
ethz.date.deposited
2018-01-22T13:24:50Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2018-05-28T11:55:55Z
ethz.rosetta.lastUpdated
2018-11-07T09:37:53Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
dc.identifier.olduri
http://hdl.handle.net/20.500.11850/232359
dc.identifier.olduri
http://hdl.handle.net/20.500.11850/265601
ethz.COinS
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