AbstractThis project utilises the continuously-growing mouse incisor as a model to study mesenchymal stem cell heterogeneity and behaviour in vivo. Key MSC subpopulations located in a niche at the apical end of the incisor are studied in development, adult homeostasis and when the incisor is challenged to understand molecular mechanisms regulating growth and activation of MSCs/reservoir cells in repair and regeneration and to inform the development of new regenerative dental therapies.
MSC sub-populations marked by Thy1/CD90, Gli1, Sox10, LepR, and Nestin are studied using genetic lineage tracing with single and multicolour reporter mice and immunofluorescence. Heterogeneity of apical mesenchyme niche is further investigated using single-cell RNA sequencing.
Results from experiments with adult incisors suggest that the MSC niche undergoes changes with ageing and while some sub-populations continue to produce differentiated odontoblasts at a constant rate throughout the life of the animal, significant differences are observed in the contribution of Thy1-positive MSCs which decreases with age and the contribution of LepR-positive MSCs which increases with age.
When incisors are challenged, the discrete Thy1 sub-population expands and is the main contributor to the re-establishment of homeostasis in clipped incisors. Quiescent cells in the most proximal mesenchyme marked by Celsr1 act as a reservoir in the rapid response of the MSC niche to the clipping by providing more Thy1 MSCs and are possibly regulated by an autonomic mechanism via adrenergic receptors. Dental pulp mesenchyme of clipped and unclipped incisors is analysed using RNA sequencing to identify signals involved in the activation of reservoir cells in regeneration and repair.
These results give insights for understanding the MSC microenvironment in the dental pulp and have implications for developing regenerative therapies harnessing the potential of specifically-targeted endogenous stem cells to accelerate repair.
|Date of Award||1 Apr 2019|
|Supervisor||Paul Sharpe (Supervisor) & Cynthia Andoniadou (Supervisor)|