Abstract
Insight into human tooth epithelial stem cells and their biology is sparse. Tissue-derived organoid models typically replicate the tissue’s epithelial stem cell compartment. Here, we developed a first-in-time epithelial organoid model starting from human tooth. Dental follicle (DF) tissue, isolated from unerupted wisdom teeth, efficiently generated epithelial organoids that were long-term expandable. The organoids displayed a tooth epithelial stemness phenotype similar to the DF’s epithelial cell rests of Malassez (ERM), a compartment containing dental epithelial stem cells. Single-cell transcriptomics reinforced this organoid-ERM congruence, and uncovered novel, mouse-mirroring stem cell features. Exposure of the organoids to epidermal growth factor induced transient proliferation and eventual epithelial-mesenchymal transition, highly mimicking events taking place in the ERM in vivo. Moreover, the ERM stemness organoids were able to unfold an ameloblast differentiation process, further enhanced by transforming growth factor-β (TGFβ) and abrogated by TGFβ receptor inhibition, thereby reproducing TGFβ's known key position in amelogenesis. Interestingly, by creating a mesenchymal-epithelial composite organoid (assembloid) model, we demonstrated that the presence of dental mesenchymal cells (i.e. pulp stem cells) triggered ameloblast differentiation in the epithelial stem cells, thus replicating the known importance of mesenchyme-epithelium interaction in tooth development and amelogenesis. Also here, differentiation was abrogated by TGFβ receptor inhibition. Together, we developed novel organoid models empowering the exploration of human tooth epithelial stem cell biology and function as well as their interplay with dental mesenchyme, all at present only poorly defined in humans. Moreover, the new models may pave the way to future tooth-regenerative perspectives.
Highlights
Teeth play essential roles in food mastication and speech
Since the human tooth epithelial stem cell niche is undefined, we tested growth and signaling factors shown to play a role in tooth development, including sonic hedgehog (SHH), fibroblast growth factors (FGFs) and insulin-like growth factor-1 (IGF1) [23, 24]
Given the importance of mesenchyme-epithelium interactions during tooth development including ameloblast differentiation/amelogenesis [4, 54], we addressed the question whether addition of dental mesenchymal cells had an impact on ameloblast differentiation of the epithelial organoids
Summary
Teeth play essential roles in food mastication and speech. tooth physiology is more and more highlighted to impact body health and disease [1,2,3]. Stem cells of the mesenchymal compartments such as dental pulp and periodontal ligament (PDL) have substantially been characterized, knowledge on human tooth epithelial stem cells regarding presence, phenotype and biological function is scarce [4]. Some indications for their existence have been found in the epithelial cell rests of Malassez (ERM), a network of epithelial cells that is present in the dental follicle (DF) which encloses unerupted teeth and upon tooth eruption remains present in the PDL around the root [5].
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