Tooth Regeneration
Introduction Teeth are an important component of the oral cavity that affects other functions of the body such as digestion. However, unlike other parts of the body, teeth as a whole do not naturally regenerate once lost (Ravindran and George, 2015). Presently, missing teeth are usually replaced with artificial prostheses that can never fully restore the physiological functions of a natural tooth (Zhao and Chai, 2015). Over the past few decades, researchers have had a keen interest in stem cell-mediated regeneration to functionally restore organs and, more recently, teeth, potentially yielding many applications of tooth regeneration in dental and oral medicine (Aurrekoetxea, 2015).
But before studying how stem cells can be used to restore …show more content…
lost teeth, an understanding of how teeth form in the first place must be established. Therefore, this paper will explore how teeth naturally develop starting from embryonic life, then will discuss the different approaches to teeth regeneration currently being investigated, discussing the first general stem cells used and the different types of dental stem cells.
Background: The Structure of a Human Tooth
Human teeth are composed of four main mineralized tissues: enamel, dentin, cementum, and bone (Jheon et al., 2013). The innermost part of the tooth is the soft dental pulp, a highly vascularized and innervated tissue that provides vitality to the tooth. The pulp responds to bacterial infection and injury, transmits mechanical stimuli (Ravindran, 2015), as well as houses odontoblast stem cells that naturally help restore damaged dentin. (Jheon et al., 2013). If the pulp gets infected, due to poor oral hygiene or certain medical treatments, the current treatment is root canal therapy, which results in the complete removal of the soft tissue pulp, thus making the tooth essentially “dead” (Ravindran, 2015). Once removed, the pulp with its nerves will not be able to regenerate naturally. Teeth also have a periodontal ligament that attaches the tooth to the underlying bone, while the gingiva, or the gum, is an oral mucosa that overlies the alveolar bone (Jheon et al., 2013).
Stages of Tooth Development
Tooth development primarily relies on the interaction between two main tissues, epithelium and mesenchyme (Miletich, 2004).
Epithelium is derived from the oral ectoderm, while the only source of mesenchyme able to sustain tooth development is derived from multipotential stem cells called cranial neural crest cells (NCCs) (Jheon et al., 2013; Miletich, 2004). Some cranial NCCs located in the dental pulp, which have the unique capacity to produce mesenchymal cells that are capable of differentiating into highly specialized cell types, maintain plasticity into their postnatal life; this gives NCCs potential for regeneration (Miletich, 2004). There are four types of neural crest cells: cranial (bone/cartilage), cardiac, vagal, and trunk; these show just how multipotential these cells really are, making them great for regenerative medicine (Zhao and Chai, …show more content…
2015).
The ectoderm, the outermost layer of cells/tissues of an embryo, is one of the three primary components of an embryo in its early stages, the other two being the mesoderm and the endoderm (Wikipedia). In vertebrates, there are three parts to the ectoderm: the external ectoderm, the neural crest, and the neural tube; the latter two are collectively known as the neuroectoderm (Wikipedia). The neural crest- derived mesenchyme has critical information to model tooth shape and eventually forms facial and jaw skeletons, as well as the dentin, the dental pulp, the alveolar bone, and the periodontal ligament ; it also gives rise to the periodontium, the surrounding tissues that hold teeth in position. (Jheon et al., 2013; Miletich, 2004). The site of tooth formation is based on the expression of specific genes and a number of signaling pathways provided by the oral epithelium (Jheon et al., 2013: Miletich, 2004). These signaling molecules establish large cellular fields competent to form a specific tooth shape, mono or multi cuspid; they also define two types of mesenchyme: oral, which are capable of forming teeth, and non-oral (Miletich, 2004). Soon thereafter, the oral epithelium thickens and during what is called the bud stage, its cells multiply to form a dental lamina that invaginates into the underlying ectomesenchyme, which condenses around epithelial buds (Jheon et al., 2013; Miletich, 2004). Dental papilla is then generated from condensed mesenchymal cells underneath the forming epithelial bud called odontoblasts, which secrete dentin (Miletich, 2004). From this point onward, the dental mesenchyme regulates the formation of the the tooth’s shape.
Following this is the cap stage, when the now extended epithelial bud surrounds the dental papilla and the dental mesenchyme cells to form the dental follicle or sac (Jheon et al., 2013). Also, now present in the dental epithelium is the primary enamel knot, a signaling center that regulates the shape of the crown by folding the tip of the epithelial bud. For multi cuspid teeth, there are secondary foldings of the epithelial bud during the bell stage, where the tooth germ site increases in size and the final shape of the tooth becomes more apparent. (Jheon et al., 2013; Miletich, 2004). Secondary enamel knots determine sites of tooth cusp formation (Jheon et al., 2013). In order to undergo this cusp morphogenesis, the primary and secondary enamel knots maintain a balance between cell proliferation and apoptosis by expressing a wide range of signaling molecules (Miletich, 2004).
Finally, tooth specific cell types begin to differentiate; odontoblasts, located at the periphery of the pulp, produce the dentin, while ameloblasts, localized at the periphery of the enamel layer, produce the enamel (Jheon et al., 2013; Miletich, 2004). It is important to note that the tooth’s layer of enamel can not self-repair because ameloblasts are no longer present after tooth eruption (Miletich, 2004).
After the formation of the crown, which is the part of the tooth covered by the enamel, the root begins to form simultaneously with the eruption of the tooth. Derived from the dental follicle are the cementum, periodontal ligament, and alveolar bone, which are all involved in anchoring the tooth to the jaw (Jheon et al., 2013). The stem cells of the dental follicle can differentiate and form the cementum (Zhao and Chai, 2015).
Although tooth development begins in the embryonic stage of life, tooth morphogenesis continues postnatally, with tooth eruption occurring soon after birth and a second dentition developing during the first twenty years of life (Miletich, 2004).
What are Stem Cells? Stem cells are a special type of unspecialized clonogenic cells that have the potential to differentiate into different kinds of cells with specialized functions (Bethesda, 2015). In addition to multilineage differentiation, stem cells have the ability to continuously self-renew themselves (Gronthos, 2002; Zhao and Chai, 2015). They also play a key role in the repair and replenishment of tissues, replacing cells that are lost by “normal wear and tear or by injury and disease” (Bethesda, 2015). This amazing capability to regenerate damaged tissues have made stem cells of particular interest to researchers interested in regenerative medicine (Zhao and Chai, 2015).
There are three primary types of stem cells known to researchers as of today: embryonic stem cells, “somatic” or adult stem cells, and induced pluripotent stem cells (iPSC; Bethesda, 2015). An adult tissue is considered regenerative if tissue-specific stem cell populations are able to maintain their numbers and have the capacity to differentiate into distinct cell lineages (Miletich, 2004). Stem cell- based tissue engineering is an emerging field of biomedical science that utilizes stem cells to restore damaged tissues (Zhao and Chai, 2015). Although stem cells were identified over forty years ago, dental stem cells were first studied in the early 21st century. Early studies of these dental stem cells borrowed mechanisms from past bone marrow mesenchymal stem cell research (Zhao and Chai, 2015).
Bone Marrow MSCs
It was discovered by Alexander Friedenstein in the 1960s that cells from the bone marrow host stromal MSCs, similar to fibroblasts, that can give rise to multilineage osteocytes (blood cells) while retaining self-renewability, as well as being able to adhere to the culture plate (Zhao and Chai, 2015). Earlier studies of the blood-forming “hematopoietic” stem cells inspired the similar approach of identifying markers, like CD271, CD146, CD90, and CD105, to identify MSCs (Zhao and Chai, 2015).
Literature Cited
Aurrekoetxea M, Garcia-Gallastegui P, Irastorza I, Luzuriaga J, Uribe-Etxebarria V, Unda F and Ibarretxe G (2015) Dental pulp stem cells as a multifaceted tool for bioengineering and the regeneration of craniomaxillofacial tissues.
Front. Physiol. 6:289. doi: 10.3389/fphys.2015.00289
Retrieved from: http://journal.frontiersin.org/article/10.3389/fphys.2015.00289/abstract
Bethesda, MD (2015) Stem Cell Basics: Introduction. In Stem Cell Information [World Wide Web site]. : National Institutes of Health, U.S. Department of Health and Human Services, 2015 [cited Thursday, December 17, 2015] Available at S. Gronthos, J. Brahim, W. Li, L.W. Fisher, N. Cherman, A. Boyde, P. Den Besten, P. Gehron Robey, and S. Shi (2002) Stem Cell Properties of Human Dental Pulp Stem Cells. Journal of Dental Research. J DENT RES 2002 81: 531 Retrieved from: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.335.5026&rep=rep1&type=pdf
Jheon, A., Seidel, K., Biehs, B. (2013)From molecules to mastication: the development and evolution of teeth, Wiley Interdiscip Rev Biol. 2013: 2(2): 165-183. doi:10.1002/wdev.63. Retrieved from:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632217/pdf/nihms369246.pdf
Miletich, I. and Sharpe, P. T. (2004), Neural crest contribution to mammalian tooth formation. Birth Defects Research Part C: Embryo Today: Reviews, 72: 200–212. doi: 10.1002/bdrc.20012.
Retrieved from: http://onlinelibrary.wiley.com/doi/10.1002/bdrc.20012/abstract
Ravindran S and George A (2015) Biomimetic extracellular matrix mediated somatic stem cell differentiation: applications in dental pulp tissue regeneration. Front. Physiol. 6:118. doi: 10.3389/fphys.2015.00118 Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404808/pdf/fphys-06-00118.pdf Zhao, H. and Chai, Y. (2015) Stem Cells in Teeth and Craniofacial Bones, Journal of Dental Research, Vol 94(11) 1495-1501
Retrieved from: http://jdr.sagepub.com/content/94/11/1495.long#ref-58
But before studying how stem cells can be used to restore …show more content…
lost teeth, an understanding of how teeth form in the first place must be established. Therefore, this paper will explore how teeth naturally develop starting from embryonic life, then will discuss the different approaches to teeth regeneration currently being investigated, discussing the first general stem cells used and the different types of dental stem cells.
Background: The Structure of a Human Tooth
Human teeth are composed of four main mineralized tissues: enamel, dentin, cementum, and bone (Jheon et al., 2013). The innermost part of the tooth is the soft dental pulp, a highly vascularized and innervated tissue that provides vitality to the tooth. The pulp responds to bacterial infection and injury, transmits mechanical stimuli (Ravindran, 2015), as well as houses odontoblast stem cells that naturally help restore damaged dentin. (Jheon et al., 2013). If the pulp gets infected, due to poor oral hygiene or certain medical treatments, the current treatment is root canal therapy, which results in the complete removal of the soft tissue pulp, thus making the tooth essentially “dead” (Ravindran, 2015). Once removed, the pulp with its nerves will not be able to regenerate naturally. Teeth also have a periodontal ligament that attaches the tooth to the underlying bone, while the gingiva, or the gum, is an oral mucosa that overlies the alveolar bone (Jheon et al., 2013).
Stages of Tooth Development
Tooth development primarily relies on the interaction between two main tissues, epithelium and mesenchyme (Miletich, 2004).
Epithelium is derived from the oral ectoderm, while the only source of mesenchyme able to sustain tooth development is derived from multipotential stem cells called cranial neural crest cells (NCCs) (Jheon et al., 2013; Miletich, 2004). Some cranial NCCs located in the dental pulp, which have the unique capacity to produce mesenchymal cells that are capable of differentiating into highly specialized cell types, maintain plasticity into their postnatal life; this gives NCCs potential for regeneration (Miletich, 2004). There are four types of neural crest cells: cranial (bone/cartilage), cardiac, vagal, and trunk; these show just how multipotential these cells really are, making them great for regenerative medicine (Zhao and Chai, …show more content…
2015).
The ectoderm, the outermost layer of cells/tissues of an embryo, is one of the three primary components of an embryo in its early stages, the other two being the mesoderm and the endoderm (Wikipedia). In vertebrates, there are three parts to the ectoderm: the external ectoderm, the neural crest, and the neural tube; the latter two are collectively known as the neuroectoderm (Wikipedia). The neural crest- derived mesenchyme has critical information to model tooth shape and eventually forms facial and jaw skeletons, as well as the dentin, the dental pulp, the alveolar bone, and the periodontal ligament ; it also gives rise to the periodontium, the surrounding tissues that hold teeth in position. (Jheon et al., 2013; Miletich, 2004). The site of tooth formation is based on the expression of specific genes and a number of signaling pathways provided by the oral epithelium (Jheon et al., 2013: Miletich, 2004). These signaling molecules establish large cellular fields competent to form a specific tooth shape, mono or multi cuspid; they also define two types of mesenchyme: oral, which are capable of forming teeth, and non-oral (Miletich, 2004). Soon thereafter, the oral epithelium thickens and during what is called the bud stage, its cells multiply to form a dental lamina that invaginates into the underlying ectomesenchyme, which condenses around epithelial buds (Jheon et al., 2013; Miletich, 2004). Dental papilla is then generated from condensed mesenchymal cells underneath the forming epithelial bud called odontoblasts, which secrete dentin (Miletich, 2004). From this point onward, the dental mesenchyme regulates the formation of the the tooth’s shape.
Following this is the cap stage, when the now extended epithelial bud surrounds the dental papilla and the dental mesenchyme cells to form the dental follicle or sac (Jheon et al., 2013). Also, now present in the dental epithelium is the primary enamel knot, a signaling center that regulates the shape of the crown by folding the tip of the epithelial bud. For multi cuspid teeth, there are secondary foldings of the epithelial bud during the bell stage, where the tooth germ site increases in size and the final shape of the tooth becomes more apparent. (Jheon et al., 2013; Miletich, 2004). Secondary enamel knots determine sites of tooth cusp formation (Jheon et al., 2013). In order to undergo this cusp morphogenesis, the primary and secondary enamel knots maintain a balance between cell proliferation and apoptosis by expressing a wide range of signaling molecules (Miletich, 2004).
Finally, tooth specific cell types begin to differentiate; odontoblasts, located at the periphery of the pulp, produce the dentin, while ameloblasts, localized at the periphery of the enamel layer, produce the enamel (Jheon et al., 2013; Miletich, 2004). It is important to note that the tooth’s layer of enamel can not self-repair because ameloblasts are no longer present after tooth eruption (Miletich, 2004).
After the formation of the crown, which is the part of the tooth covered by the enamel, the root begins to form simultaneously with the eruption of the tooth. Derived from the dental follicle are the cementum, periodontal ligament, and alveolar bone, which are all involved in anchoring the tooth to the jaw (Jheon et al., 2013). The stem cells of the dental follicle can differentiate and form the cementum (Zhao and Chai, 2015).
Although tooth development begins in the embryonic stage of life, tooth morphogenesis continues postnatally, with tooth eruption occurring soon after birth and a second dentition developing during the first twenty years of life (Miletich, 2004).
What are Stem Cells? Stem cells are a special type of unspecialized clonogenic cells that have the potential to differentiate into different kinds of cells with specialized functions (Bethesda, 2015). In addition to multilineage differentiation, stem cells have the ability to continuously self-renew themselves (Gronthos, 2002; Zhao and Chai, 2015). They also play a key role in the repair and replenishment of tissues, replacing cells that are lost by “normal wear and tear or by injury and disease” (Bethesda, 2015). This amazing capability to regenerate damaged tissues have made stem cells of particular interest to researchers interested in regenerative medicine (Zhao and Chai, 2015).
There are three primary types of stem cells known to researchers as of today: embryonic stem cells, “somatic” or adult stem cells, and induced pluripotent stem cells (iPSC; Bethesda, 2015). An adult tissue is considered regenerative if tissue-specific stem cell populations are able to maintain their numbers and have the capacity to differentiate into distinct cell lineages (Miletich, 2004). Stem cell- based tissue engineering is an emerging field of biomedical science that utilizes stem cells to restore damaged tissues (Zhao and Chai, 2015). Although stem cells were identified over forty years ago, dental stem cells were first studied in the early 21st century. Early studies of these dental stem cells borrowed mechanisms from past bone marrow mesenchymal stem cell research (Zhao and Chai, 2015).
Bone Marrow MSCs
It was discovered by Alexander Friedenstein in the 1960s that cells from the bone marrow host stromal MSCs, similar to fibroblasts, that can give rise to multilineage osteocytes (blood cells) while retaining self-renewability, as well as being able to adhere to the culture plate (Zhao and Chai, 2015). Earlier studies of the blood-forming “hematopoietic” stem cells inspired the similar approach of identifying markers, like CD271, CD146, CD90, and CD105, to identify MSCs (Zhao and Chai, 2015).
Literature Cited
Aurrekoetxea M, Garcia-Gallastegui P, Irastorza I, Luzuriaga J, Uribe-Etxebarria V, Unda F and Ibarretxe G (2015) Dental pulp stem cells as a multifaceted tool for bioengineering and the regeneration of craniomaxillofacial tissues.
Front. Physiol. 6:289. doi: 10.3389/fphys.2015.00289
Retrieved from: http://journal.frontiersin.org/article/10.3389/fphys.2015.00289/abstract
Bethesda, MD (2015) Stem Cell Basics: Introduction. In Stem Cell Information [World Wide Web site]. : National Institutes of Health, U.S. Department of Health and Human Services, 2015 [cited Thursday, December 17, 2015] Available at S. Gronthos, J. Brahim, W. Li, L.W. Fisher, N. Cherman, A. Boyde, P. Den Besten, P. Gehron Robey, and S. Shi (2002) Stem Cell Properties of Human Dental Pulp Stem Cells. Journal of Dental Research. J DENT RES 2002 81: 531 Retrieved from: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.335.5026&rep=rep1&type=pdf
Jheon, A., Seidel, K., Biehs, B. (2013)From molecules to mastication: the development and evolution of teeth, Wiley Interdiscip Rev Biol. 2013: 2(2): 165-183. doi:10.1002/wdev.63. Retrieved from:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632217/pdf/nihms369246.pdf
Miletich, I. and Sharpe, P. T. (2004), Neural crest contribution to mammalian tooth formation. Birth Defects Research Part C: Embryo Today: Reviews, 72: 200–212. doi: 10.1002/bdrc.20012.
Retrieved from: http://onlinelibrary.wiley.com/doi/10.1002/bdrc.20012/abstract
Ravindran S and George A (2015) Biomimetic extracellular matrix mediated somatic stem cell differentiation: applications in dental pulp tissue regeneration. Front. Physiol. 6:118. doi: 10.3389/fphys.2015.00118 Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404808/pdf/fphys-06-00118.pdf Zhao, H. and Chai, Y. (2015) Stem Cells in Teeth and Craniofacial Bones, Journal of Dental Research, Vol 94(11) 1495-1501
Retrieved from: http://jdr.sagepub.com/content/94/11/1495.long#ref-58