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The role of KRT5+ progenitors in chronic otitis media

Chandrasekharan, Deepak P.; (2020) The role of KRT5+ progenitors in chronic otitis media. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Background: Chronic inflammation of the middle ear, known as chronic otitis media, is a debilitating condition of unknown aetiology that causes hearing loss in children and adults. Recent work suggests the epithelial lining of the middle ear cavity may play a role in the disease process. The hypothesis is that abnormal proliferation and differentiation of keratin-5(KRT5)-positive progenitor cells results in a maladaptive epithelial remodelling. The work here characterises KRT5+ progenitor cells and explores their contribution to middle ear epithelial homeostasis in health and chronic otitis media with effusion (COME). Methods: Murine middle ear epithelial cells from the Fbxo11Jf/+ model of COME and healthy controls were isolated by enzymatic dissociation and used for colony forming assays, immunocytochemistry and flow cytometry. Cells were grown at air-liquid interface to analyse differentiation potential and a 3Dspheroid assay was used to analyse single cell differentiation. KRT5-Cre- ERT2;R26R-Confetti multicolour reporter mice were generated to perform lineage tracing to visualise middle ear epithelial homeostasis in vivo. Results: Middle ear epithelium has cells with progenitor cell capacity that are KRT5+. These make up approximately 7% of the epithelial compartment and may have a dorso-ventral asymmetry of distribution that reverses in Fbxo11Jf/+ mice. Differentiation assays show middle ear progenitors from Fbxo11Jf/+ mice have aberrant differentiation potential with reduced bipotent differentiation ability. 3D whole-mount visualisation of the middle ear from multicolour reporter mice shows the presence of distinct KRT5+ progenitor derived clones in multiple regions of the middle ear. Conclusion: This work provides further support that KRT5+ cells are progenitor cells of the middle ear epithelium with bipotent differentiation capacity and thus may maintain the epithelium in health. These progenitor characteristics seem to be perturbed in the Fbxo11Jf/+ mouse model of COME. Understanding the mechanism underlying these changes offers the potential to identify new therapeutic targets.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of KRT5+ progenitors in chronic otitis media
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10118735
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