Heterogeneity and Developmental Connections between Cell Types Inhabiting Teeth

Abstract

Every tissue is composed of multiple cell types that are developmentally, evolutionary and functionally integrated into the unit we call an organ. Teeth, our organs for biting and mastication, are complex and made of many different cell types connected or disconnected in terms of their ontogeny. In general, epithelial and mesenchymal compartments represent the major framework of tooth formation. Thus, they give rise to the two most important matrix-producing populations: ameloblasts generating enamel and odontoblasts producing dentin. However, the real picture is far from this quite simplified view. Diverse pulp cells, the immune system, the vascular system, the innervation and cells organizing the dental follicle all interact, and jointly participate in transforming lifeless matrix into a functional organ that can sense and protect itself. Here we outline the heterogeneity of cell types that inhabit the tooth, and also provide a life history of the major populations. The mouse model system has been indispensable not only for the studies of cell lineages and heterogeneity, but also for the investigation of dental stem cells and tooth patterning during development. Finally, we briefly discuss the evolutionary aspects of cell type diversity and dental tissue integration.

Keywords: ameloblast; cell heterogeneity; dental development; dental pulp; odontoblast; odontogenesis; stem cells; tooth.

Figure 1

Developmental analogies between the continuously growing incisor and brachyodont tooth development. Different developmental stages in a brachyodont (non-continuously growing) tooth (A) are analogous to different transversal projections of a hypselodont (continuously growing) tooth along a proximal-distal axis (B,C). The labial surface of the mouse continuously growing incisor, usually described as a “crown analog,” is covered by enamel. This is in contrast to the lingual side, the “root analog,” which is covered by cementum. Gray arrows indicate directions of movements in the mesenchymal and the epithelial cell populations. (ERM—epithelial cell rests of Malassez; HERS—Hertwig's epithelial root sheath).

Figure 2

Cell heterogeneity in tooth. Both epithelium and mesenchyme preserve their stem cell niches (A,B). In the labial cervical loop, stem cells are located in the stellate reticulum from where they produce transit-amplifying cells that are inserted into the dental epithelium and later differentiate into inner (IEE) and outer enamel epithelium (OEE). Only the labial IEE can give rise to fully functional enamel-producing ameloblasts. In contrast to dental epithelium, dental mesenchymal stem cells are derived from both glial cells and peri-arteriole cells located in a neurovascular bundle. Mesenchymal stem cells give rise to both odontoblasts and pulp cell progeny. Moreover, peri-arteriole cells can give rise to NG2⁺ pericytes. The pulp is formed and maintained by complex interactions between many different cell types, including circulatory system-related cells (endothelium, smooth muscles, pericytes, immune cells), nerves with axons and glia or odontoblasts, and related pulp cells (C). Close to the tip of the incisor, increased apoptosis can be observed. Pericytes in the tip give rise to matrix-producing cells which help to seal the incisor opening (D). A close structural relationship between odontoblasts and immune cells like macrophages and dendritic cells is seen in teeth (C,D). After differentiation into secretory ameloblasts, when the full volume of enamel matrix is produced, these cells undergo a transition phase (E). During this, about 25% of the ameloblasts die through apoptosis. The remaining ones become less elongated, and during the maturation phase they release inorganic compounds and mineralize enamel rods to full extent. After the maturation phase, only about 50% of the initial amount of ameloblasts remain viable to form a protective layer which finally disappears after tooth eruption. Ameloblasts during the secretory phase have a characteristic movement pattern (shown by arrows in E). Through combined movements outwards (pushed by matrix secretion) and toward the tip (pushed by newly differentiated ameloblasts) they form alternating layers where one layer slides between adjacent layers that move in opposite directions. This creates a characteristic criss-cross pattern (yellow and orange arrows in E).

Figure 3

Origin of cells of the tooth. Teeth are organs composed by cells with different developmental origins. Quantitatively, most tooth tissue is of neural crest origin (A). Cells emerging from the neural crest give rise to both pulp and extra-pulpal tissue. Dental epithelium can have ectodermal and/or endodermal origin. In the adult non-continuously growing tooth, dental epithelium-derived cells are absent, leaving enamel matrix that covers the tooth crown behind (B). Continuously growing teeth maintain their SC niches and have all cell types mentioned above. In addition to the two main components, ectomesenchyme and epithelium, blood vessel-related tissue of mesodermal origin form fundamental parts of dental pulp tissue (C). (D,E) Schematically depicted representation of tissues of different origins in continuously or non-continuously growing teeth. (PDL—periodontal ligament; SC's—stem cells; ERM—epithelial cell rests of Malassez; DMSCs—dental mesenchymal stem cells).