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Wnt signalling and stem cell mobilisation in tissue injury repair

Paul Sharpe

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Medical Research Council (MRC)
Canonical Wnt signalling is involved in multiple developmental and postnatal biological processes and when disregulated is a direct cause of cancers such as colorectal cancer. Recently a new role has been identified in tissue damage repair where Wnt activity is upregulated immediately following damage in all tissues and species (both vertebrate and invertebrate) examined. Experimental abrogation of this increase in signalling activity severely impairs natural repair of tissue damage. A key response to tissue damage is the mobilisation of mesenchymal stem cells and a generic source of these cells are perivascular cells (pericytes). This proposal aims to investigate the mechanisms by which canonical Wnt activity initiates a cascade of cellular processes required for tissue damage repair. These include stem cell proliferation, cell homing (chemotaxis) and differentiation. We will use a novel, extremely tractable model system of experimemtally creating tissue damage to mouse incisor teeth. The damage responses observed in teeth are the same as those described in other tissues but incisors have a number of signficant advatages as a model system. Mouse incisors have three separate and clearly recognisable mesenchymal stem cell niches and can be easily manipulated in vivo and in vitro. We will use this system to identify the molecular pathways downstream of damage-induced Wnt activiation and by manipulating the Wnt activity following damage, determine the effects on stem cell mobilisation from the different niches.

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