title: Chronic inflammation imposes aberrant cell fate in regenerating epithelia through mechanotransduction.
abstract: Chronic inflammation is associated with a variety of pathological conditions in epithelial tissues, including cancer, metaplasia and aberrant wound healing. In relation to this, a significant body of evidence suggests that aberration of epithelial stem and progenitor cell function is a contributing factor in inflammation-related disease, although the underlying cellular and molecular mechanisms remain to be fully elucidated. In this study, we have delineated the effect of chronic inflammation on epithelial stem/progenitor cells using the corneal epithelium as a model tissue. Using a combination of mouse genetics, pharmacological approaches and in vitro assays, we demonstrate that chronic inflammation elicits aberrant mechanotransduction in the regenerating corneal epithelium. As a consequence, a YAP-TAZ/β-catenin cascade is triggered, resulting in the induction of epidermal differentiation on the ocular surface. Collectively, the results of this study demonstrate that chronic inflammation and mechanotransduction are linked and act to elicit pathological responses in regenerating epithelia.
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland 1015, Switzerland.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Nowell
authors.affiliation: Laboratory for Bio- and Nano-Instrumentation (LBNI), Institute of Bioengineering (IBI), EPFL, Lausanne, Switzerland 1015, Switzerland.
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Odermatt
authors.affiliation: University of Padua, Department of Molecular Medicine, via G. Colombo 3, 35131 Padova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Azzolin
authors.affiliation: Laboratory of Stem Cell Bioengineering (LSCB), IBI, EPFL, Lausanne, Switzerland 1015, Switzerland.
authors.forename: Sylke
authors.initials: S
authors.lastname: Hohnel
authors.affiliation: Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.affiliation: Laboratory for Bio- and Nano-Instrumentation (LBNI), Institute of Bioengineering (IBI), EPFL, Lausanne, Switzerland 1015, Switzerland.
authors.forename: Georg E
authors.initials: GE
authors.lastname: Fantner
authors.affiliation: Laboratory of Stem Cell Bioengineering (LSCB), IBI, EPFL, Lausanne, Switzerland 1015, Switzerland.
authors.forename: Matthias P
authors.identifier: http://orcid.org/0000-0002-5898-305X
authors.initials: MP
authors.lastname: Lutolf
authors.affiliation: Stem Cell Dynamics Laboratory (LDSC), IBI, EPFL, Lausanne, Switzerland 1015, Switzerland.
authors.forename: Yann
authors.initials: Y
authors.lastname: Barrandon
authors.affiliation: University of Padua, Department of Molecular Medicine, via G. Colombo 3, 35131 Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Piccolo
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland 1015, Switzerland.
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D060433:Administration, Ophthalmic; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002908:Chronic Disease; D065306:Corneal Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019573:Epithelium, Corneal / Q000187:drug effects / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007634:Keratitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics; D012038:Regeneration / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013552:Swine; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D060449:Wnt Signaling Pathway; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; C495267:CTNNB1 protein, mouse; D018797:Cell Cycle Proteins; D018836:Inflammation Mediators; C497762:Notch1 protein, mouse; D010750:Phosphoproteins; D051881:Receptor, Notch1; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051176:beta Catenin; D000217:Acyltransferases; C486363:tafazzin protein, mouse