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dc.contributor.authorRiddle, Rebecca
dc.contributor.authorJennbacken, Karin
dc.contributor.authorHansson, Kenny
dc.contributor.authorHarper, Matthew
dc.date.accessioned2022-06-09T23:30:06Z
dc.date.available2022-06-09T23:30:06Z
dc.date.issued2022-04-27
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337957
dc.description.abstractInflammatory diseases are often characterised by excessive neutrophil infiltration from the blood stream to the site of inflammation, which damages healthy tissue and prevents resolution of inflammation. Development of anti-inflammatory drugs is hindered by lack of in vitro and in vivo models which accurately represent the disease microenvironment. In this study, we used the OrganoPlate to develop a humanized 3D in vitro inflammation-on-a-chip model to recapitulate neutrophil transmigration across the endothelium and subsequent migration through the extracellular matrix (ECM). Human umbilical vein endothelial cells formed confluent vessels against collagen I and geltrex mix, a mix of basement membrane extract and collagen I. TNF-α-stimulation of vessels upregulated inflammatory cytokine expression and promoted neutrophil transmigration. Intriguingly, major differences were found depending on the composition of the ECM. Neutrophils transmigrated in higher number and further in geltrex mix than collagen I, and did not require an N-formyl-methionyl-leucyl-phenylalanine (fMLP) gradient for transmigration. Inhibition of neutrophil proteases inhibited neutrophil transmigration on geltrex mix, but not collagen I. These findings highlight the important role of the ECM in determining cell phenotype and response to inhibitors. Future work could adapt the ECM composition for individual diseases, producing accurate models for drug development.
dc.description.sponsorshipAstraZeneca-Cambridge PhD Studentship
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleEndothelial Inflammation and Neutrophil Transmigration Are Modulated by Extracellular Matrix Composition in an Inflammation-on-a-chip Model
dc.typeArticle
dc.publisher.departmentDepartment of Pharmacology
dc.date.updated2022-03-11T12:18:19Z
prism.publicationNameScientific Reports
dc.identifier.doi10.17863/CAM.85363
dcterms.dateAccepted2022-03-11
rioxxterms.versionofrecord10.1038/s41598-022-10849-x
rioxxterms.versionVoR
dc.contributor.orcidHarper, Matthew [0000-0002-4740-637X]
dc.identifier.eissn2045-2322
rioxxterms.typeJournal Article/Review
pubs.funder-project-idNational Centre for the Replacement Refinement and Reduction of Animals in Research (NC/N002350/1)
pubs.funder-project-idBritish Heart Foundation (PG/20/12/34982)
cam.issuedOnline2022-04-27
cam.depositDate2022-03-11
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International