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Fig. 2. a Histology of sound dentine in a premolar. b Dentine tubules are numerous and wide open on the pulp side. c They are less numerous and appear more narrow at mid-distance between the pulp and the dentine-enamel junction. d Dentine tubules are very narrow and many of them appear completely obliterated upon approaching the dentine-enamel junction.

      Pulp Response to Dental Caries

      Host pulp response to dental caries is a key element in understanding the carious process and its consequences. In this regard, enamel acts as a physical mineralised barrier preventing bacterial infiltration into the dentine and pulp. Also, the underlying dentine histology, composition, and function provide significant information on how bacteria invasion is hindered by the dentine itself and how this dentine provides signalling molecules to induce dentine regeneration during the carious process. In the case of a deep carious lesion reaching the odontoblasts, the pulp tissue itself has also elaborated efficient strategies to hinder or even arrest the carious lesion progression and the bacterial infiltration into the pulp.

      Dentine Histology at the Dentine Enamel Junction Is Different from that of Deep Dentine

Dentine has a unique histological tubular appearance. The tubules close to the dental pulp are numerous and wide open. Their diameter decreases gradually as they get away from the pulp and become very narrow or completely obliterated upon approaching the dentine-enamel junction (Fig. 2).

      This suggests that the superficial dentine hinders bacterial infiltration when they reach the dentine surface. On the other hand, when bacteria reach the open dentine tubules they can invade the dental pulp more rapidly through the tubules. This may suggest significant consequences to the underlying pulp only if we consider the bacterial invasion consequences. However, the dental pulp established efficient protective mechanisms against this invasion.

      Dentine Matrix Contains Sequestered Signalling Molecules

While the major dentine inorganic component is hydroxyapatite, its organic matrix is mainly composed of collagen I and non-collagenous proteins such as dentine sialoprotein [18] and dentine matrix protein-1 [19]. These are involved in the initiation and the regulation of dentine mineralisation. In addition, different signalling molecules have been reported to be secreted by the odontoblasts and sequestered in the dentine matrix, mainly in an inactive form. Among others, these include transforming growth factor-β₁ (TGF-β₁), basic fibroblast growth factor (FGF-2), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) [20, 21]. During the carious dissolution of the dentine matrix, these molecules can be released and reach the underlying odontoblasts leading to the upregulation of their synthetic activity.

In addition to the responsiveness to these growth factors, recent data demonstrated that odontoblasts act as sensor cells as they express transient potential channel receptors. These receptors allow the odontoblast to be responsive to the external stimulations, such as noxious heat, noxious cold, as well as chemical and mechanical stimulations [22]. Thus, upon stimulation, odontoblasts synthesise a new tertiary dentine at the pulp periphery facing the stimulation site. This focally secreted dentine can also be deposited within the dentine tubules to decrease their permeability to cariogenic bacteria and their toxins, leading to the protection of the underlying pulp.

Thus, odontoblasts represent the first defence mechanism in case of carious lesion development. Indeed, these cells also express receptors called Toll-like receptors (TLRs) 2 and 4 [23, 24], which recognise specific structures on Gram-positive and Gram-negative bacteria, respectively. These TLRs belong to a big family of pattern recognition receptors that are activated after contact with common molecules on the pathogen surface. In moderate carious injuries, TLRs 2 are highly expressed in the underlying odontoblasts [25]. Upon activation, these TLRs induce the secretion of antimicrobial molecules such as β-defensins and nitric oxide by the odontoblasts which have an antibacterial effect against S. mutans, thus limiting cariogenic bacteria progression towards the pulp [26]. Also, upon activation of their receptors, odontoblasts secrete proinflammatory chemokines which lead to dendritic cell recruitment in order to eliminate the pathogenic agents [27].

Overall, in the case of moderate dentine carious lesions, the odontoblasts act as a barrier exerting antimicrobial effects and initiating the secretion of a tertiary dentine to protect the underlying pulp (Fig. 3).

However, in the case of severe and rapidly progressive carious lesions, tertiary dentine focal synthesis may not be enough and bacteria may destroy the newly synthesised tertiary dentine, reach the underlying pulp, and induce an inflammatory reaction (Fig. 4).

      The Dental Pulp Defence Strategies

When the odontoblastic barrier is destroyed by the carious lesion and either bacteria or their toxins reach the underlying pulp, a tertiary dentine secretion can still be observed. This dentine, which is secreted after the odontoblast destruction, is synthesised by another cell type originating for the differentiation of adult pulp stem cells. This reparative dentine usually contains fewer tubules than the physiological one. This might decrease the bacterial infiltration or their toxins to the underlying pulp. While little was known about the cells secreting this dentine, the discovery of adult stem cells within the dental pulp provided a significant step forward. Indeed, all dental pulps in permanent and primary teeth and at all ages comprise, at least, a population of adult stem cells [28]. This was first demonstrated in a culture system of cells isolated from the pulps of third molars, where pulp cells were able to produce a mineral matrix with molecular and mineral characteristics of dentine [29]. Additionally, when isolated with specific mesenchymal stem cell

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