Hypes and Hopes of Stem Cell Therapies in Dentistry: a Review

One of the most exciting advances in life science research is the development of 3D cell culture systems to obtain complex structures called organoids and spheroids. These 3D cultures closely mimic in vivo conditions, where cells can grow and interact with their surroundings. This allows us to better study the spatio-temporal dynamics of organogenesis and organ function. Furthermore, physiologically relevant organoids cultures can be used for basic research, medical research, and drug discovery. Although most of the research thus far focuses on the development of heart, liver, kidney, and brain organoids, to name a few, most recently, these structures were obtained using dental stem cells to study in vitro tooth regeneration. This review aims to present the most up-to-date research showing how dental stem cells can be grown on specific biomaterials to induce their differentiation in 3D. The possibility of combining engineering and biology principles to replicate and/or increase tissue function has been an emerging and exciting field in medicine. The use of this methodology in dentistry has already yielded many interesting results paving the way for the improvement of dental care and successful therapies. Graphical abstract

Comparative Analysis of Dental Pulp and Periodontal Stem Cells: Differences in Morphology, Functionality, Osteogenic Differentiation and Proteome

Dental stem cells are heterogeneous in their properties. Despite their common origin from neural crest stem cells, they have different functional capacities and biological functions due to niche influence. In this study, we assessed the differences between dental pulp stem cells (DPSC) and periodontal ligament stem cells (PDLSC) in their pluripotency and neuroepithelial markers transcription, morphological and functional features, osteoblast/odontoblast differentiation and proteomic profile during osteogenic differentiation. The data were collected in paired observations: two cell cultures, DPSC and PDLSC, were obtained from each donor. Both populations had the mesenchymal stem cells surface marker set exposed on their membranes but differed in Nestin (a marker of neuroectodermal origin) expression, morphology, and proliferation rate. OCT4 mRNA was revealed in DPSC and PDLSC, while OCT4 protein was present in the nuclei of DPSC only. However, transcription of OCT4 mRNA was 1000–10,000-fold lower in dental stem cells than in blastocysts. DPSC proliferated at a slower rate and have a shape closer to polygonal but they responded better to osteogenic stimuli as compared to PDLSC. RUNX2 mRNA was detected by qPCR in both types of dental stem cells but RUNX2 protein was detected by LC-MS/MS shotgun proteomics only in PDLSC suggesting the posttranscriptional regulation. DSPP and DMP1, a marker gene of odontoblastic type of osteogenic differentiation, were transcribed in DPSC but not in PDLSC samples. Our results prove that DPSC and PDLSC are different in their biology and therapeutic potential: DPSC are a good candidate for osteogenic or odontogenic bone-replacement cell-seeded medicines, while fast proliferating PDLSC are a prospective candidate for other cell products.

Intertwined Signaling Pathways Governing Tooth Development: A Give-and-Take Between Canonical Wnt and Shh

Teeth play essential roles in life. Their development relies on reciprocal interactions between the ectoderm-derived dental epithelium and the underlying neural crest-originated mesenchyme. This odontogenic process serves as a prototype model for the development of ectodermal appendages. In the mouse, developing teeth go through distinct morphological phases that are tightly controlled by epithelial signaling centers. Crucial molecular regulators of odontogenesis include the evolutionarily conserved Wnt, BMP, FGF and sonic hedgehog (Shh) pathways. These signaling modules do not act on their own, but are closely intertwined during tooth development, thereby outlining the path to be taken by specific cell populations including the resident dental stem cells. Recently, pivotal Wnt-Shh interaction and feedback loops have been uncovered during odontogenesis, showing conservation in other developing ectodermal appendages. This review provides an integrated overview of the interplay between canonical Wnt and Shh throughout mouse tooth formation stages, extending from the initiation of dental placode to the fully formed adult tooth.

The effects and potential applications of concentrated growth factor in dentin–pulp complex regeneration

The dentin–pulp complex is essential for the long-term integrity and viability of teeth but it is susceptible to damage caused by external factors. Because traditional approaches for preserving the dentin–pulp complex have various limitations, there is a need for novel methods for dentin–pulp complex reconstruction. The development of stem cell-based tissue engineering has given rise to the possibility of combining dental stem cells with a tissue-reparative microenvironment to promote dentin–pulp complex regeneration. Concentrated growth factor, a platelet concentrate, is a promising scaffold for the treatment of dentin–pulp complex disorders. Given its characteristics of autogenesis, convenience, usability, and biodegradability, concentrated growth factor has gained popularity in medical and dental fields for repairing bone defects and promoting soft-tissue healing. Numerous in vitro studies have demonstrated that concentrated growth factor can promote the proliferation and migration of dental stem cells. Here, we review the current state of knowledge on the effects of concentrated growth factor on stem cells and its potential applications in dentin–pulp complex regeneration.

Sinking Our Teeth in Getting Dental Stem Cells to Clinics for Bone Regeneration

Dental stem cells have been isolated from the medical waste of various dental tissues. They have been characterized by numerous markers, which are evaluated herein and differentiated into multiple cell types. They can also be used to generate cell lines and iPSCs for long-term in vitro research. Methods for utilizing these stem cells including cellular systems such as organoids or cell sheets, cell-free systems such as exosomes, and scaffold-based approaches with and without drug release concepts are reported in this review and presented with new pictures for clarification. These in vitro applications can be deployed in disease modeling and subsequent pharmaceutical research and also pave the way for tissue regeneration. The main focus herein is on the potential of dental stem cells for hard tissue regeneration, especially bone, by evaluating their potential for osteogenesis and angiogenesis, and the regulation of these two processes by growth factors and environmental stimulators. Current in vitro and in vivo publications show numerous benefits of using dental stem cells for research purposes and hard tissue regeneration. However, only a few clinical trials currently exist. The goal of this review is to pinpoint this imbalance and encourage scientists to pick up this research and proceed one step further to translation.

Characteristics, Classification, and Application of Stem Cells Derived from Human Teeth

Since mesenchymal stem cells derived from human teeth are characterized as having the properties of excellent proliferation, multilineage differentiation, and immune regulation. Dental stem cells exhibit fibroblast-like microscopic appearance and express mesenchymal markers, embryonic markers, and vascular markers but do not express hematopoietic markers. Dental stem cells are a mixed population with different sensitive markers, characteristics, and therapeutic effects. Single or combined surface markers are not only helpful for understanding the subpopulation of mixed stem cell populations according to cell function but also for improving the stable treatment effect of dental stem cells. Focusing on the discovery and characterization of stem cells isolated from human teeth over the past 20 years, this review outlines the effect of marker sorting on cell proliferation and differentiation ability and the assessment of the clinical application potential. Classified dental stem cells from markers and functional molecules can solve the problem of heterogeneity and ensure the efficacy of cell therapy strategies including dentistry, neurologic diseases, bone repair, and tissue engineering.