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Whole-tooth regeneration: what are the problems/knowledge gaps that need to be solved?

Image credit: Dr. Alan Carr, https://creativecommons.org/licenses/by/2.0/

Shubhankar Kulkarni
Shubhankar Kulkarni Sep 07, 2020
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What are the currently used therapies for tooth regeneration? What are the problems/ inadequacies they face? How can we overcome them?

The teeth repair treatments, although reliable and effective, offer only a repair of the tooth structure, replacing the original tissue for inert materials. In many cases, some biological functions of teeth, such as proprioception and aesthetics are compromised. Also, these treatments have failure rates (lower than most of the other medical treatment available), but they require replacements or repetitions over time.

Regenerative medicine is usually described as a field on translational research, focused on tissue engineering. The approach is intended to recover or regenerate the original tissues and functions compromised by disease. We, humans, are diphyodonts, which means we replace our teeth only once. Histology suggests that we may have the ability to generate a third dentition, but this potential is inhibited by some unknown molecular mechanisms. The ultimate goal of whole-tooth regeneration is to provide a living, functional, and biocompatible tissue. However, we need to understand the mechanisms that regulate embryonic tooth development and mimic the natural cascade of signaling that occurs during organ formation.

Therefore, we should also list the knowledge gaps in the understanding of the underlying mechanisms of tooth generation. What experiments need to be performed to overcome them? Alternatively, what are the prospective therapies that you think have the potential to enable complete tooth regeneration and why?

[1]Balic A. Biology Explaining Tooth Repair and Regeneration: A Mini-Review. Gerontology [Internet]. 2018;64(4):382–8. Available from: https://www.karger.com/Article/FullText/486592

[2]Smith EE, Yelick PC. Progress in Bioengineered Whole Tooth Research: from Bench to Dental Patient Chair. Curr Oral Heal Reports [Internet]. 2016 Dec 5;3(4):302–8. Available from: http://link.springer.com/10.1007/s40496-016-0110-2

[3]Mitsiadis TA, Harada H. Regenerated teeth: the future of tooth replacement. An update. Regen Med [Internet]. 2015 Jan;10(1):5–8. Available from: https://www.futuremedicine.com/doi/10.2217/rme.14.78

[4]Yang L, Angelova Volponi A, Pang Y, Sharpe PT. Mesenchymal Cell Community Effect in Whole Tooth Bioengineering. J Dent Res [Internet]. 2017 Feb 7;96(2):186–91. Available from: http://journals.sagepub.com/doi/10.1177/0022034516682001

Creative contributions

Using mesenchymal stem cells and 3D-tissue engineering

Antonio Carusillo
Antonio Carusillo Sep 12, 2020
Currently, for oral diseases, dental prostheses, periodontal treatment and dental implants, autogenous bone transplantation is the main treatment. However, it is hampered by sources availability, engraftment yield and morbidity. But most importantly this is a way to slow down tissue decay, rather than promoting its regeneration (1). Therefore a strategy enabling tissue regeneration would be highly requested. Mesenchymal stem cells (MSCs), which can be isolated from different tissues and possess self-renewal and multiple differentiation potential, play an essential role in organ development and postnatal repair (2). Presently, there are two main strategies of MSC-based bone and dental regeneration: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering. Regenerative medicine with dental tissue-derived cells has been increasingly developed. MSCs have currently proposed as an attractive cell source for bone and tooth regeneration due to their potential for differentiation into osteoblasts or odontoblasts, ability to modulate systematic immunity, and lack of ethical controversies. Despite the enormous efforts devoted to exogenous MSC transplantation for tissue regeneration, an alternative therapeutic strategy is to take advantage of endogenous MSCs within specific tissues to harness their self-renewal potential to produce specific cell types. Clinical trials have demonstrated that both endogenous and exogenous MSCs hold enormous promise in regenerative medicine for bone and tooth among which: - Bone marrow MSCs (BMMSCs) have received much attention. Studies have shown promising therapeutic potential in osteopenia and bone defects when combined with cytotherapy or tissue engineering (3). - Adipo-derived MSCs (ADMSCs) (4). These can differential into various cell types, including osteocytes, chondrocytes. They are also easy to access than BMMSCs. They have been showing to improve tissue maintenance undergoing pathological condition - Dental stem cells (DSCs) including dental pulp stem cells (DPSCs) they had shown therapeutic potential as well. DPSCs were the first human dental tissue-derived MSCs to be identified from dental pulp tissue of permanent teeth and deciduous teeth besides being an easy-to-access source they also feature immunomodulatory characteristics which may allow for a less T cell alloreactivity associated with hematopoietic or solid-organ allogeneic transplantation (5). These interesting cell types may be combined with different technologies. A possible strategy could be scaffold technology which is based on seeding target cells on degradable materials such as natural molecules and synthetic polymers constructing a three-dimensional (3D) engineered tissue for the regeneration of damaged ones (6). Bioengineering has contributed to large-scale tissue regeneration for damaged tissues, this method has shown high utility in three-dimensional tissue engineering technology, and these preparations have been used in clinical applications including bone and cartilage regenerative therapies. This scaffold-based method may be practical for controlling tooth shape and size; however, the fundamental problems regarding the regeneration of tooth itself have not been resolved. The presence of residual scaffold material after in vivo transplantation is considered to be the cause of the low frequency of tooth formation and the irregularity of the resulting tooth tissue structures e.g. the enamel-dentin complex and the cell arrangement of ameloblast/odontoblast lineages. Complete development of proper tooth structure using scaffolds requires the formation of complex junctions between the enamel, dentin and cementum that result from accurate spatiotemporal cell gradients of ameloblasts, odontoblasts and cementoblasts as well as natural tooth development(7). The cell aggregation method is a typical bioengineering protocol employed for the reconstitution of a bioengineered organ germ to reproduce the epithelial-mesenchymal interactions that occur during organogenesis (7). Previous studies have reported that bioengineered cell aggregates -from the ectodermal origin - gave rise to the proper tissue structure and cellular arrangements once transplanted in vivo. In the dental field, many researchers have isolated single stem cells from dental epithelial and mesenchymal tissues. It has been reported that bioengineering cell aggregates containing dental epithelial and mesenchymal stem cells using the cellular centrifugation have the potential for tooth germ formation after in vivo transplantation. Even when bioengineered cell aggregate was mixed with epithelial and mesenchymal stem cells isolated from tooth germ, the correct tooth structure could be generated by the self-reorganisation through the cell rearrangement of epithelial and mesenchymal cells. Although this technique partially replicated tooth organogenesis, further improvements in the frequency of bioengineered tooth development and correct tissue formation have been required(8). A bioengineered mature tooth is another attractive concept. A bioengineered tooth germ would be transplanted into the tooth loss region and would develop into a functioning mature tooth. Transplantation of a bioengineered tooth unit has also been proposed as a viable option to repair the large resorption defects in the alveolar bone after tooth loss To enable these whole tooth regenerative strategies, it will be important first to develop techniques for the manipulation of cells in three dimensions to reconstruct bioengineered tooth using completely dissociated epithelial and mesenchymal cells in vitro. This may be achieved for example by engineering a tooth germ. Development of a bioengineered tooth germ using completely dissociated single stem cells from epithelial and mesenchymal tissues of incisor or molar tooth germ. This has been attempted using MSCs from mice. It was possible to achieve three-dimensional cell compartmentalization of epithelial and mesenchymal cells at a high cell density in a collagen gel. This bioengineered tooth germ can achieve initial tooth development with the appropriate cell-to-cell compaction between epithelial and mesenchymal cells in vitro organ culture. The bioengineered tooth germ generates a structurally correct tooth after transplantation in organ culture in vitro as well as in vivo(9). Compared with exogenous MSC transplantation, tissue regeneration mediated by endogenous MSCs could less expensive and labour intensive and avoids surgical injury and rejection risk. Nevertheless, in mammals, the regenerative capabilities of endogenous MSCs progressively decline during postnatal development, leading to limited innate repairing capacity (10). Moreover, under pathological conditions, such as osteoporosis and periodontitis, the function of endogenous MSCs is severely impaired, as characterized by decreased proliferation and osteogenic differentiation capabilities. Several studies have investigated the complex signalling pathways underlying gene expression regulations and MSCs regenerative properties. These include rapamycin signalling, Notch signalling, nuclear transcription factor-kappaB (NF-KB) signalling and Wnt signalling. Based on these shreds of evidence, different compounds acting on the pathways mentioned above have been designed and proved to be in rescuing endogenous MSC impairment and promoting bone and dental regeneration (11). Also, another strategy to rescue and recall endogenous MSCs is via the modulation of the microenvironment where stem cells reside in vivo, this besides using compounds or hormone therapies can be achieved by transplantation of healthy MSCs (12). MSCs beside having a regenerative effect may also play a role in modulating the systemic inflammatory condition via cell-cell interaction or paracrine mechanism also contributes to their therapeutic efficiency. Physiologically, the niche where MSCs reside consists of a variety of tissue components, cell populations and soluble factors, which tightly regulate the behaviours of MSCs. Under pathological conditions, such as osteoporosis and periodontitis, both the viability and differentiation of MSCs are seriously impaired, leading to disease aggravation and impaired tissue healing. Furthermore, in cytotherapy and tissue engineering, the microenvironments of donors and recipients play a pivotal role in determining the regenerative efficacy of transplanted MSC. In addition to accumulating evidence identifying the prominence of the microenvironment in MSC-based regenerative therapies, solutions have been developed, such as the improvement of the microenvironment to restore endogenous MSC function, the enhancement of MSC resistance to a diseased microenvironment, and the restoration of the recipient microenvironment to benefit transplanted MSCs. Notably, after being transplanted into recipients, MSCs act as potent microenvironment modulators in both tissue engineering and cytotherapy (13). References: 1- Sakkas, A., Wilde, F., Heufelder, M. et al. Autogenous bone grafts in oral implantology—is it still a “gold standard”? A consecutive review of 279 patients with 456 clinical procedures. Int J Implant Dent 3, 23 (2017). https://doi.org/10.1186/s40729-017-0084-4 2- Imran Ullah, Raghavendra Baregundi Subbarao, Gyu Jin Rho; Human mesenchymal stem cells - current trends and future prospective. Biosci Rep 1 April 2015; 35 (2): e00191. doi: https://doi.org/10.1042/BSR20150025 3- Hang Lin, Jihee Sohn, He Shen, Mark T. Langhans, Rocky S. Tuan, Bone marrow mesenchymal stem cells: Aging and tissue engineering applications to enhance bone healing, Biomaterials, Volume 203, 2019, Pages 96-110, ISSN 0142-9612, https://doi.org/10.1016/j.biomaterials.2018.06.026. 4- Frese L, Dijkman P, E, Hoerstrup S, P: Adipose Tissue-Derived Stem Cells in Regenerative Medicine. Transfus Med Hemother 2016;43:268-274. doi: 10.1159/000448180 5- Casagrande L, Cordeiro MM, Nör SA, Nör JE. Dental pulp stem cells in regenerative dentistry. Odontology. 2011;99(1):1-7. doi:10.1007/s10266-010-0154-z 6- Henkel, J., & Hutmacher, D. W. (2013). Design and fabrication of scaffold-based tissue engineering, BioNanoMaterials, 14(3-4), 171-193. doi: https://doi.org/10.1515/bnm-2013-0021 7- Stem cell-based biological tooth repair and regeneration Volponi, Ana Angelova et al. Trends in Cell Biology, Volume 20, Issue 12, 715 – 722 8- Chalisserry EP, Nam SY, Park SH, Anil S. Therapeutic potential of dental stem cells. Journal of Tissue Engineering. January 2017. doi:10.1177/2041731417702531 9- Kazuhisa Nakao, Takashi Tsuji, Dental regenerative therapy: Stem cell transplantation and bioengineered tooth replacement, Japanese Dental Science Review, Volume 44, Issue 1, 2008, Pages 70-75, ISSN 1882-7616, https://doi.org/10.1016/j.jdsr.2007.11.001. 10- Pittenger, M.F., Discher, D.E., Péault, B.M. et al. Mesenchymal stem cell perspective: cell biology to clinical progress. npj Regen Med 4, 22 (2019). https://doi.org/10.1038/s41536-019-0083-6 11- Song B, Chi Y, Li X, Du W, Han Z, -B, Tian J, Li J, Chen F, Wu H, Han L, Lu S, Zheng Y, Han Z: Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway. Cell Physiol Biochem 2015;36:1991-2002. doi: 10.1159/000430167 12- Zheng, C., Chen, J., Liu, S. et al. Stem cell-based bone and dental regeneration: a view of microenvironmental modulation. Int J Oral Sci 11, 23 (2019). https://doi.org/10.1038/s41368-019-0060-3 13- Salgado Antonio J., Sousa Joao C., Costa Bruno M., Pires Ana O., Mateus-Pinheiro António, Teixeira F. G., Pinto Luisa, Sousa Nuno, Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities, Frontiers in Cellular Neuroscience, Vol. 9, 2014, p. 249, doi: 10.3389/fncel.2015.00249
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Could human deciduous pulp stem cell (hDPSC) implantation be used?

Subash Chapagain
Subash Chapagain Oct 15, 2020
Dental pulp, serving as the formative and supportive organ for dentin, is critical for tooth longevity. Human pulp stem cells (PSCs) include dental pulp stem cells (DPSCs) isolated from dental pulp tissues of human extracted permanent teeth and stem cells from human exfoliated deciduous teeth (SHED) .

The potential of hDPSCs in tooth regeneration has been explored in a study that used autologous stem cells from deciduous teeth. When hDPSCs were implanted, the researchers were able to regenerate the dental pulp along with the odontoblast layer, blood vessels, and nerves in a pair of animal models. Pushed by these positive results, the same treatment was applied for 26 patients who had pulp necrosis due to traumatic dental injuries. hDPSC implantation was found to cause regeneration of three-dimensional pulp tissue equipped with blood vessels and sensory nerves when observed after 12 months of treatment. Moreover, no adverse side-effects or secondary complications associated with the treatment were observed, which further supports the idea of using this approach for partial tooth-regeneration .

Intraoral pulp‐dentin complex regeneration approach is capable of forming reparative dentin-like tissue on the pre-existing dentin layer, which can eventually cause whole-tooth regeneration. The precursor triad of DPSCs, dentin matrix protein (DMP-1), and collagen scaffold can induce collagen matrix formation and enriched angiogenesis in the pulp chamber . Also, a group found that human tooth slice as a source of latent signalling molecules could be used for pulp-dentin regeneration. When the scientists seeded SHED in poly-L-lactic acid (a material for scaffold) to transplant a tooth slice onto it in immunocompromised mice, they found that after 14-28 days, physiologic pulp tissue developed, along with neo-dentin. Using this methodology, regeneration within the entire length of the root canal can be achieved on the basis of PSC transplantation .

[1]Miura, M., Gronthos, S., Zhao, M., Lu, B., Fisher, L. W., Robey, P. G., & Shi, S. (2003). SHED: Stem cells from human exfoliated deciduous teeth. Proceedings of the National Academy of Sciences, 100(10), 5807–5812. https://doi.org/10.1073/pnas.0937635100

[2]Xuan, K., Li, B., Guo, H., Sun, W., Kou, X., He, X., Zhang, Y., Sun, J., Liu, A. Liao, L., Liu, S., Liu, W., Hu, C., Shi, S., & Jin, Y. (2018). Deciduous autologous tooth stem cells regenerate dental pulp after implantation into injured teeth. Science Translational Medicine, 10(455), eaaf3227. https://doi.org/10.1126/scitranslmed.aaf3227

[3]Prescott RS, Alsanea R, Fayad MI, et al. In vivo generation of dental pulp‐like tissue by using dental pulp stem cells, a collagen scaffold, and dentin matrix protein 1 after subcutaneous transplantation in mice. J Endod. 2008;34(4):421‐426.

[4]Cordeiro MM, Dong Z, Kaneko T, et al. Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. J Endod. 2008;34(8):962‐969.

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Find Out How Supernumerary Teeth Are Generated

Jamila Sep 07, 2020
Humans are classed as diphyodonts meaning that we can only replace our teeth once in our lifetime. However, some people have the ability to produce 3rd generation teeth. This is what you call supernumerary teeth, more teeth than what is normally expected, a “wisdom tooth” is an example of this. [1] It seems that there’s a certain mechanism used to stop the development of teeth after the second set (which we also don’t know about). But as mentioned earlier, there are some rare individuals who seem to surpass this and can produce more teeth! Does this mean they can somehow avoid “the stopping mechanism”, what exactly allows these individuals to get more teeth? So far, the research has shown that supernumerary teeth can sometimes form due to mutations in genes that give rise to disorders such as Gardner’s syndrome, cleidocranial dysplasia, or other health conditions. [2] Some researchers suggest that supernumerary teeth arise due to the presence of the third dentition.[3] Recently, Takahashi and colleagues proposed two potential theories as to why supernumerary teeth are produced in the first place. The researchers say it could be to do with tooth rudiments or the odontogenic epithelial stem cells. [1] In regards to the first theory, they suggest that the preservation of tooth rudiments could lead to the development of supernumerary teeth. During the initial stages of tooth development, dental buds can form but these may not progress onto the next stage, and could even be removed by apoptosis. [1] In one study, suppressing USAG-1 was able to regenerate teeth by preventing apoptosis of the rudimentary tooth germ. [4] This information is really helpful and gives us more knowledge of tooth regeneration. Perhaps a therapy could be developed to target and activate the third dentition in order to regenerate teeth. Future ideas/questions •Perhaps a CRISPR-screen could be conducted of candidate genes that may cause extra teeth? This would help us understand which other pathways are involved in producing the extra teeth, and this could lay the foundation for a tooth regeneration treatment. •What mechanisms stop the third dentition from becoming a full set of teeth? •Could there be any unwanted side effects of activating the third dentition? •Could we inhibit any other genes related to apoptosis in order to activate tooth regeneration? •Could we upregulate genes that inhibit apoptosis to form new teeth? References 1. Takahashi, Katsu, et al. "Development of tooth regenerative medicine strategies by controlling the number of teeth using targeted molecular therapy." Inflammation and Regeneration 40.1 (2020): 1-9. 2. Takahashi, Katsu, et al. "Two non-syndromic cases of multiple supernumerary teeth with different characteristics and a review of the literature." Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28.3 (2016): 250-254. 3. Kiso, Honoka, et al. "Third Dentition Is the Main Cause of Premolar Supernumerary Tooth Formation." Journal of dental research 98.9 (2019): 968-974. 4. Murashima-Suginami, Akiko, et al. "Enhanced BMP signaling results in supernumerary tooth formation in USAG-1 deficient mouse." Biochemical and biophysical research communications 369.4 (2008): 1012-1016.
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General comments

Darko Savic
Darko Savic3 years ago
Sounds like we are 30% there https://youtu.be/en79wtbytvk

The video is referring to this Chinese study https://stm.sciencemag.org/content/10/455/eaaf3227
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