Understanding the Role of Wnt Signaling During Repair of the Tympanic Membrane

    Student thesis: Doctoral ThesisDoctor of Philosophy


    Tympanic membrane (TM) perforations are a common and debilitating issue. Although many perforations heal on their own, some do not and become chronic. It has been hypothesised that a stem or progenitor cell population must reside in the tympanic membrane and be responsible for ability to repair. These putative stem cells have been shown to reside in niches confined to the manubrium, annulus, and more recently the mallear folds. Currently the only treatment options to treat chronic perforations involve invasive surgery, although alternative approaches are beginning to be investigated. To aid the identification of new therapeutics, it is important to understand more about the cells in the different layers of the tympanic membrane and the signals that drive homeostasis and repair. One potential signalling pathway that has not yet been investigated in the ear drum is the Wnt pathway. Wnt signalling has been implicated in regeneration in many parts of the body and Wnt responding cells reside in the presumptive stem cell niches in the tympanic membrane. The tympanic membrane is composed of three layers with a different embryonic origin: the ectodermal epithelium, a middle mesenchymal layer derived from the neural crest and an inner mucosal layer with an endodermal origin. All three layers are involved in healing, but their exact contribution, timing and interaction are not fully understood. Using markers for the different layers, as well as reporter mouse lines, we mapped, and lineage traced the contribution of the different cell types of the TM during repair and linked each process with Wnt responding cell types.

    Using Axin2cre lineage tracing mice, Wnt-responding cells in the tympanic membrane were shown to exhibit many stem-like qualities, and contributed to the repair of tympanic membrane perforations, but not to the epithelial homeostasis of the tissue. To further interrogate the role of Wnt signaling, loss-of-function Ctnnb1;Axin2creERT2;tomato in vivo mouse models, and novel drug treated in vitro explants were used to highlight the effects of manipulating Wnt signaling on repair. When Wnt signaling was perturbed, the healing of the tympanic membrane was disrupted, illustrating its key role in repair.

    Understanding how Wnt signalling is involved in this process is of fundamental importance not only to enhance knowledge of how repair takes place but also in the discovery of novel pharmacological approaches to treat human acute and chronic TM perforations.
    Date of Award1 Mar 2024
    Original languageEnglish
    Awarding Institution
    • King's College London
    SupervisorAbigail Tucker (Supervisor) & Dan Jiang (Supervisor)

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