Ameloblasts
Fabricator of the Dental Realm
Credit: Art by Nelly Aghekyan. Set in motion by Dr. Emanuele Petretto. Words by Dr. Eshita Paul. Coordinator: Dr. Masia Maksymowicz, Series Director: Dr. Radhika Patnala
#Extraordinarycelltypes #sciart #lifescience
Like Ogden Nash said ‘Some tortures are physical and some are mental, But the one that is both is dental’, there are no comforters for a toothache. In today’s society, where appearance matters a lot, one must preserve the enamel of his teeth at every sacrifice. Though dental enamel is the hardest tissue in the human body that protects the dental crown from external wear and tear, it still needs to be safeguarded (1). This is because once the teeth are fully formed, the specialized dental cells called ameloblasts, which secrete and deposit enamel, undergo apoptosis, making it impossible for the body to regenerate or repair the damaged enamel of an erupted tooth (2). This makes the teeth more vulnerable to breakage or loss (3).
Origin and life cycle
Ameloblasts or enamel-producing cells are columnar hexagonal cells that originate from the dental epithelium facing the layer of odontoblasts and have distinct morphological features that vary at each stage of tooth development. Differentiation of ameloblasts is promoted by more developed odontoblasts and stratum intermedium cells through chemical signals in the form of BMP-4 and FGF8/9 (4). The life cycle of an ameloblast starts with the morphogenic stage and sequentially goes through organizing, formative, maturative, protective, and desmolytic stages. Secretory and maturation ameloblasts exhibit temporal expression of specific enamel genes that carry out stage-specific tasks (5).
In the secretory phase of enamel formation, ameloblasts are highly polarised with an average height of ~70 µm and diameter of ~5 µm (5) and characterized by the presence of Tomes’ processes (triangular cell extensions that penetrate the enamel matrix at the distal end of the cell by which the matrix of enamel is released). The transition stage from secretory to mature is rapid. During this stage ameloblasts shrink in length, begin losing Tomes’ process and ~25% of them die (6,7). In the maturation stage, ameloblasts are only ~40 µm in height. They undergo cyclic changes in morphology between ruffle-ended (RA) and smooth-ended (SA) appearance in synchronized groups, manifesting as bands of comparable morphology obliquely across the crown’s circumference (8). During enamel formation, 50% of the ameloblasts commit to apoptosis. The remaining half goes into cell death at the end of the process, leaving no option for secondary growth or regeneration of enamel.
Amelogenesis
The reciprocal interactions between epithelial-mesenchymal cells that influence teeth development take place sequentially, with each stage having its own unique anatomical and cellular characteristics. The dental epithelium (also known as the competent epithelium) coming from the ectoderm, is the initial origin of the odontogenic potential. This potential can trigger tooth formation in any mesenchyme that originates from the neural crest (9).
Making the enamel
Dental epithelium gives rise to ameloblasts — the primary cells of the enamel organ (4). They regulate the intricate process of enamel formation and mineralization (known as amelogenesis) with great precision (10). Enamel is a tissue with a hierarchically organized structure composed of very elongated hydroxyapatite (HA, Ca10(PO4)6(OH)2) crystallites (11). The highly polarized secretory ameloblast cells surround the growing enamel tissue in a monolayer, moving as a single developing line in predetermined directions and putting down a soft extracellular proteinaceous matrix that acts as a template for the creation of crystals (12). As the mineralization of enamel progresses, the matrix protein secretion decreases. These matrix proteins (mostly amelogenins, enamelins, ameloblastins, and tuftelins) are subsequently broken down in the maturation stage and eliminated via proteolysis, also by ameloblasts (6). Among these proteins, amelogenin is essential to the development of enamel as it hydrolyzes from the secretory to the maturation phases and directs the creation of early hydroxyapatite crystals.
Keeping connection in enamel
In order to maintain intercellular connections, ameloblasts create a semi-permeable barrier, with the secretory or the distal end forming extracellular crystals under specific pH conditions and the basal or the proximal end receiving nutrients and ions from blood vessels. Ameloblasts use a variety of cellular processes such as pH control, proteolysis, endocytosis, and influencing the movement of minerals and ions to coordinate crystal development in this unique environment.
Layering and striations- association with the circadian rhythm
The mature enamel has three layers: the enamel-dentin junction (EDJ), outer enamel surface (OES), and Hunter-Schreger bands (HSB) (13). The HA fibers in the OES and HSBs are highly ordered, unlike the randomly distributed HA crystals in dentin (14). The growth direction of enamel prisms from the dentin surface is determined by the movement of an ameloblast. Two types of enamel prisms that are diagonally expanded from the EDJ help build the cross-lamellar structure in HSBs. Enamel prisms are made up of a bundle of nanometer-wide HA fibers oriented in the same direction. The complex designs are formed from bent fibrous structures, but their creation method and crystallographic structures are still unknown.
Research on the enamel matrix suggests that enamel creation is not only dependent on developmental regulation but also incremental. Enamel cross-striations (which indicate daily deposition of enamel) and long-period Retzius striae are examples of this incremental development. These enamel cross-striations are a result of the diurnal pattern in ameloblast activity with the peak secretion of enamel proteins at around 8 pm (15,16).
Ameloblasts in disease
The production of normal enamel by healthy ameloblasts can be disturbed by various factors such as genetic mutations, trauma, illnesses, chemical exposure, malnutrition, and hormone dysregulation. These factors can cause abnormal enamel formation due to aberrant cellular behavior caused by intrinsic regulatory systems. Genetic disorders of ameloblasts include Junctional epidermolysis bullosa, Amelogenesis imperfecta, Tricho-dento-osseous syndrome, while non-hereditary disorders include Ameloblastoma, Ameloblastic fibroma, odontomas, which lack any defined prevention.
Amelogenesis Imperfecta (AI) is a prevalent hereditary enamel disease that affects approximately 1 in 14,000 to 16,000 children in the USA. It is a group of inherited congenital diseases that lead to quantitative or qualitative defects in tooth enamel. It is also known as Hereditary Enamel Dysplasia or Hereditary Brown Enamel. The mode of inheritance can be autosomal dominant, autosomal recessive, or X-linked. At least 18 causal genes have been found, including those encoding enamelin, ameloblastin, tuftelin, MMP-20, and kallikrein — 4. People with AI have reduced chewing function, increased tooth sensitivity, and poor aesthetics, which often lead to social avoidance and low self-esteem.
Hope for the patients
Currently, there is no established standard of care for patients suffering from enamel defects or loss. A multidisciplinary approach might be beneficial where patients can have their dental function and aesthetic appearance restored with a precise diagnosis, careful planning of their course of treatment, and a committed team approach comprising several dental specialties. Recent advancements in regenerative dentistry have shown the potential of stem cell-based treatments. A multidisciplinary research team from the University of Washington in Seattle is working to discover a method for creating durable enamel that is comparable to natural teeth by identifying the main signaling pathways that ameloblasts and support cells use to communicate during fetal development when human ameloblasts are differentiated in vitro from iPSCs (3). With this breakthrough, biomimetic approaches can be used to conserve tooth structure and vitality, bringing the “Century of Living Fillings” within reach.
Recognizing and appreciating the labs working in this space
- DenBesten Lab, University of California San Francisco, USA (https://denbesten.ucsf.edu/)
- Alan Mighel, University of Leeds, UKl (https://medicinehealth.leeds.ac.uk/dentistry/staff/604/alan-mighell)
- Janet Moradian-Oldak, University of Southern California, USA (https://oldaklab.usc.edu/)
- Michael Paine,University of Southern California, USA (https://painelab.usc.edu/)
- Prof. Aharon Palmon, The Hebrew University, Israel (https://en-research.huji.ac.il/people/aharon-palmon)
- Yong-Hee P. Chun,UT Health San Antonio, USA (https://directory.uthscsa.edu/academics/profile/chuny)
- Ivo Lambrichts, Hasselt University, Belgium (https://www.uhasselt.be/en/instituten-en/biomed-en/cardiometabolic-science/ivo-lambrichts-laboratory-for-histology-and-regeneration-historegen)
- Dr. Anamaria Balic, University of Zurich, Switzerland (https://www.zzm.uzh.ch/en/research/staff/balic-anamaria.html)
- Dr. Hannele Ruohola-Baker, University of Washington, USA (https://sites.uw.edu/ytz/)
- Dr. Hai Zhang, University of Washington, USA (https://dental.washington.edu/people/hai-zhang/)
References
1. Lacruz RS, Habelitz S, Wright JT, Paine ML. Dental Enamel Formation and Implications for Oral Health and Disease. Physiological Reviews. 2017 Jul;97(3):939–93.
2. Park SJ, Bae HS, Cho YS, Lim SR, Kang SA, Park JC. Apoptosis of the reduced enamel epithelium and its implications for bone resorption during tooth eruption. J Mol Hist. 2013 Feb 1;44(1):65–73.
3. Alghadeer A, Hanson-Drury S, Patni AP, Ehnes DD, Zhao YT, Li Z, et al. Single-cell census of human tooth development enables generation of human enamel. Developmental Cell. 2023 Oct 23;58(20):2163–2180.e9.
4. Matalová E, Lungová V, Sharpe P. Chapter 26 — Development of Tooth and Associated Structures. In: Vishwakarma A, Sharpe P, Shi S, Ramalingam M. https://www.sciencedirect.com/science/article/pii/B9780123971579000308
5. Smith CE. Cellular and chemical events during enamel maturation. Crit Rev Oral Biol Med. 1998;9(2):128–61.
6. Hu JCC, Chun YHP, Al Hazzazzi T, Simmer JP. Enamel formation and amelogenesis imperfecta. Cells Tissues Organs. 2007;186(1):78–85.
7. Smith CE, Warshawsky H. Quantitative analysis of cell turnover in the enamel organ of the rat incisor. Evidence for ameloblast death immediately after enamel matrix secretion. Anat Rec. 1977 Jan;187(1):63–98.
8. Reith EJ, Boyde A. The arrangement of ameloblasts on the surface of maturing enamel of the rat incisor tooth. J Anat. 1981 Oct;133(Pt 3):381–8.
9. Lacruz RS, Habelitz S, Wright JT, Paine ML. Dental Enamel Formation and Implications for Oral Health and Disease. Physiol Rev. 2017 Jul 1;97(3):939–93.
10. Simmer JP, Richardson AS, Hu YY, Smith CE, Ching-Chun Hu J. A post-classical theory of enamel biomineralization… and why we need one. Int J Oral Sci. 2012 Sep;4(3):129–34.
11. Bres EF, Steuer P, Voegel JC, Frank RM, Cuisinier FJG. Observation of the loss of the hydroxyapatite sixfold symmetry in a human fetal tooth enamel crystal. Journal of Microscopy. 1993;170(2):147–54.
12. Deutsch D, Catalano-Sherman J, Dafni L, David S, Palmon A. Enamel matrix proteins and ameloblast biology. Connect Tissue Res. 1995;32(1–4):97–107.
13. Tabuce R, Seiffert ER, Gheerbrant E, Alloing-Séguier L, von Koenigswald W. Tooth Enamel Microstructure of Living and Extinct Hyracoids Reveals Unique Enamel Types Among Mammals. J Mammal Evol. 2017 Mar 1;24(1):91–110.
14. Cox BN. How the tooth got its stripes: patterning via strain-cued motility. Journal of The Royal Society Interface. 2013 Jul 6;10(84):20130266.
15. Zheng L, Seon YJ, Mourão MA, Schnell S, Kim D, Harada H, et al. Circadian rhythms regulate amelogenesis. Bone. 2013 Jul;55(1):158–65.
16. Zheng L, Ehardt L, McAlpin B, Imad A, Kim D, Papagerakis S, et al. The Tick Tock of Odontogenesis. Exp Cell Res. 2014 Jul 15;325(2):83–9.
17. Tamgadge S, Tamgadge A, Agre B. Ameloblasts in Health and Disease. Dentistry and Medical Research. 2021 Jun;9(1):5.
18. Chaudhary M, Dixit S, Singh A, Kunte S. Amelogenesis imperfecta: Report of a case and review of literature. J Oral Maxillofac Pathol. 2009;13(2):70–7.
About the author:
Dr. Eshita Paul
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Paul did her Ph.D. in Biochemical Engineering (Constructor University, Germany) studying the outer membrane channels and efflux pumps of Gram-negative bacteria in the context of antibiotic resistance. Currently, she is working on pediatric rare genetic disorders at Centre for DNA Fingerprinting and Diagnostics, India. Dr. Paul is passionate about scientific storytelling and an ardent admirer of scientific illustrations. She enjoys listening to podcasts and decorating the home in free time.
About the artist:
NELLY AGHEKYAN
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
