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MSCs in tooth repair

Adult teeth possess a natural repair process that acts to restore mineralized dentine following damage. Mild damage to dentine that does not penetrate into the underlying pulp stimulates odontoblasts in the immediate vicinity to generate new dentine, called reactionary dentine, in response to the damage. When lesions are more severe and penetrate the pulp, odontoblasts in the vicinity are destroyed and the tooth is at risk of infection. In this case, the resident MSCs are mobilized to differentiate into odontoblast-like cells that generate a form of dentine, called reparative dentine, that creates a bridge to protect the exposed pulp and repair the dentine (Smith et al., 1995; Sloan and Smith, 2007). Genetic lineage tracing in mice shows that reparative odontoblasts are formed from pericyte- and glia-derived MSCs in both molar and incisor damage repair (Feng et al., 2011; Kaukua et al., 2014). In both cases, the proximity of pericytes and glial cells to the damaged odontoblasts and pulp cells provides a local source of MSCs. Interestingly, in incisors, damage also stimulates the MSCs in the growth niche, which is at a distance from the site of damage, suggesting that all sources of these stem cells are able to receive and respond to signals released at the site of damage (Feng et al., 2011). Thus, it seems that damage provides a generic, indiscriminate stimulus to which all dental MSCs respond, regardless of origin, function or location. This presumably ensures that the damage is repaired quickly and suggests that the origin of the stem cell-derived odontoblasts that carry out the repair is irrelevant.

Pericyte-derived odontoblast cells have also been shown to play a role in the continuous repair process that occurs in the adult mouse incisor (Pang et al., 2016). Continuous growth and wear are balanced in the mouse incisor to maintain the optimum tooth size. However an unfortunate consequence of the abrasion and sharpening of the tips is that the soft tissue pulp in the tooth core is exposed to the oral cavity and the tooth is thus prone to infection. To prevent this exposure, a process of continuous pulp mineralization occurs at the tip, which produces a layer of mineral covering the exposed pulp. The mineral is dentine-like in composition and has been termed restorative dentine (Pang et al., 2016). In common with dentine repair processes in non-growing teeth, restorative dentine is a rapidly generated mineral that is produced by pericyte-derived odontoblast-like cells. However, unlike other repair processes, the formation of restorative dentine does not appear to be specifically stimulated by tooth damage, but is a continuous process that occurs even in the absence of damage (Pang et al., 2016).

The signals that mobilize the dental MSCs and stimulate their differentiation are poorly understood, but are known to involve the release of sequestered TGF-β following physical damage and Wnt signals that regulate pulp cell apoptosis, among other functions (Hunter et al., 2015). The presence of latent TGF-β proteins in dentine tubules and its activity in promoting reparative dentine formation has recently been exploited in a potential clinical device involving the delivery of low energy laser light to stimulate liberation of TGF-β (Arany et al., 2014). Canonical (β-catenin) Wnt signalling, which is induced immediately following tissue damage, is likely to play a major role in this mesenchymal stem cell mobilization (Whyte et al., 2012).