and transplanted after mixing with hydroxyapatite/tricalcium phosphate ceramic powder subcutaneously in mice, they generated a dentine/pulp-like tissue [30]. There is converging evidence that one of the niches of these stem cells is located in the perivascular area. After pulp injury, these cells are activated and migrate to the injury site to synthesise the tertiary dentine [31]. It has been reported that TGF-β1, which can be released after the dissolution of dentine, is involved in the recruitment of these cells and their differentiation into odontoblast-like cells secreting the tertiary dentine [32].
Fig. 3. a Histology of a moderate carious lesion in a molar. It is characterised by a disorganised dentine with a loss of the typical tubular structure at the carious site. b Tertiary dentine is secreted locally by the underlying odontoblasts (od). At this stage, bacterial infiltration is arrested at a distance from the pulp, which has a normal aspect.
Additionally, recent investigations on dental pulp, which has a terminal circulation, revealed that, in addition to the systemic regulation, it has a local regulation of its vascularisation, inflammation, and regeneration. This allows the dental pulp to resist bacterial invasion by different mechanisms, as explained below.
Dental Pulp Local Regulation
It is well established that carious injury leads to pulp hypoxia. Different pulp cell types, such as fibroblasts, endothelial, and stem cells, have been reported to upregulate the synthesis of hypoxia-inducible factor, which increases the synthesis of angiogenic growth factors such as VEGF, FGF-2, and PDGF. This leads to vasodilation and the increased formation of blood vessels at the carious injury site. Overall, this increases nutrient, blood, and oxygen supply to the injured tissue. This also allows inflammatory cell recruitment to carry out phagocytosis of pathogens. After complete pulp healing, there is a downregulation of angiogenic factor secretion and a return to normoxia with normal pulp vascularisation [33].
Fig. 4. a Histology of a severe carious lesion in a molar. It is characterised by a disorganised dentine at the carious site. b Tertiary dentine is produced in the form of a bridge by the underlying odontoblasts. At this stage, bacteria infiltrated the dentine tubules (c) and the pulp, which appears inflamed and infiltrated by numerous inflammatory cells (d).
Carious injury also leads to a pulp inflammatory reaction initiated by complement activation. Complement is the name given to about 40 proteins synthesised mainly by the liver and released in the plasma. During the inflammatory process, the complement is activated, leading to the synthesis of biologically active complement fragments. These play a major role in eliminating pathogenic agents. Pulp fibroblasts have been recently reported as the only non-immune cell capable of synthesising all complement proteins [34]. After complement activation, biologically active fragments are released. Recent investigation of these fragments revealed their involvement in the pulp anti-inflammatory and regeneration processes. Indeed, pulp complement can be activated by lipoteichoic acids of Gram-positive bacteria, such as S. mutans and S. sanguinis. Upon activation, several biologically active molecules are released. Among these, C5a has been shown to be involved in the recruitment of pulp stem cells [35] and in the guidance of nerve growth to the stimulation site [36]. Another fragment, C3a, is involved in the proliferation of both pulp fibroblasts and stem cells and in guiding fibroblast migration to the stimulation site [37]. This clearly illustrates the involvement of complement in the pulp regeneration process facing bacterial infiltration during carious disease. Indeed, reparative dentine is efficient in arresting the carious injury progression (Fig. 3). This may be partially explained by the fact that pulp complement activation also leads to the synthesis of a complex molecular structure called membrane attack complex. This complex structure can be produced by the fibroblasts and has been shown not only to be fixed on S. mutans and S. sanguinis, but also to kill these cariogenic bacteria [33]. When this complex polymerises on bacteria walls, it creates numerous holes leading to the entry of electrolytes and water, which results in bacteria destruction. Thus, the fibroblasts dampen down, and may even arrest the bacterial invasion to the pulp and provide the adequate signals not only to kill cariogenic bacteria, but also to initiate the regeneration process by recruiting the stem cells and nerve regeneration.
Overall, a carious lesion should be regarded as a dynamic process. Its progression does not only depend on the bacterial infiltration and the local environment, but also on the host pulp response.
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