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Aauthor: Dr. Anil Pandey

Tooth development results from sequential and reciprocal interactions between the oral epithelium and the underlying neural crest-derived mesenchyme. The generation of dental structures and/or entire teeth in the laboratory depends upon the manipulation of stem cells and requires a synergy of all cellular and molecular events that finally lead to the formation of tooth-specific hard tissues, dentin and enamel. Although mesenchymal stem cells from different origins have been extensively studied in their capacity to form dentin in vitro, information is not yet available concerning the use of epithelial stem cells. The odontogenic potential resides in the oral epithelium and thus epithelial stem cells are necessary for both the initiation of tooth formation and enamel matrix production. Recent studies have demonstrated their wide range of plasticity and their potential use for regenerative medicine and dentistry. This article summarizes information available on the different types of dental stem cells and discusses their potential use in regenerative medicine.

Many tissues of the human body undergo normal physiological renewal. These renewing tissues have some capacity to repair damage due to disease or trauma. Recent therapeutic modalities of some diseases have taken advantage of this phenomenon and included tissue engineering in which biologic materials are employed to replace, repair, maintain, and/or enhance tissue function1. The materials required for tissue engineering include stem cells, morphogens (or growth factors) and a scaffold to guide cell growth 1-3. Stem cells have unique characteristics. They are unspecialized cells with the ability of self renewal and differentiation in response to the appropriate signal. 4,5 Adult stem cells can be categorized based on their origin into two main groups: germline and somatic stem cells . Several types of somatic stem cells have been discovered in different locations.The mesenchymal stem cells (MSCs) are found in the stroma of adult bone marrow. They are multipotential cells with ability to differentiate into osteoblasts, chondrocytes, adipocytes and even non-mesodermal tissues such as endoderm. 5,6 Due to their multipotency search for MSCs or MSCs-like cells in different tissues was carried out and resulted in the discovery of a variety of cells in many organs of the body including the tooth.

Dental stem cells have been isolated from different soft tissues of the tooth. The tooth is mainly made of hard tissues which are connected to soft tissues. The hard tissues include the dentin which is covered by enamel in the crown and cementum in the root. The dentin encloses the dental pulp which is a richly innervated, highly vascularized soft (loose connective) tissue. The tooth is attached to its bony socket by another kind of soft (dense connective) tissue, the periodontal ligament (PDL). In 2000, Gronthos et al. isolated the first MSClike cells from the human dental pulp. 7 Subsequently,four more types of MSC-like cells have been isolated from dental tissues: pulp of exfoliated deciduous teeth 8, PDL 9, apical papilla 10 and dental follicle. 11 In this review, information available on these different types of dental stem cells and their potential use in regenerative medicine are summerized.

Dental Pulp Stem Cells (DPSCs)
DPSCs were the first type of dental stem cells to be isolated. These cells were obtained by enzymatic digestion of the pulp tissue of the human impacted third molar tooth. DPSCs have a typical fibroblast-like morphology. They are clonogenic in nature and can maintain their high proliferation rate even after extensive subculturing. 7 There is no specific biomarker to identify the DPSCs. However, DPSCs express several markers including the mesenchymal and bone marrow stem cell markers, STRO-1 and CD146 as well as the embryonic stem cell marker, Oct4. Culturing DPSCs with various differentiation media demonstrated their dentinogenic, osteogenic,adipogenic, neurogenic, chondrogenic and myogenic differentiation capabilities. 12-14 Following their transplantation in animal models, DPSCs were able to maintain their self renewal and to form pulp-like tissue, odontoblast-like cells, ectopic dentin as well as reparative dentin-like and bone-like tissues. 7,12,15

The characteristic features and multilineage differentiation potential of DPSCs have established
their stem cell nature and indicated their promising role in regenerative therapy.

Stem Cells from Human Exfoliated Deciduous Teeth (SHED)
In 2003, Miura et al. 8 isolated cells from the dental pulp which were highly proliferative and clonogenic. The isolation technique was similar to those used in the isolation of DPSCs. However, there were two differences: i) the source of cells was the pulp tissue of the crown of exfoliated deciduous teeth and ii) the isolated SHEDs did not grow as individual cells, but clustered into several colonies which, after separation, grew as individual fibroblast-like cells. SHEDs have a higher proliferation rate and a higher number of colony forming cells than DPSCs. 7,8 SHEDs were found to express early mesenchymal stem cell markers (STRO-1 and CD146). 8 In addition, embryonic stem cell markers such as Oct4, Nanog, stage-specific embryonic antigens (SSEA-3, SSEA-4), and tumor recognition antigens (TRA-1-60 and TRA-1-81) were found to be expressed by SHEDs. 16

Periodontal Ligament Stem Cells (PDLSCs)

The PDL does not only anchor the tooth, but also contributes to its nutrition, homoeostasis, and repair. PDL contains different types of cells including cells which can differentiate into cementoblast and osteoblasts. 17-20 Heterogeneity and continuous remodeling of PDL is an indication for the presence of progenitor cells which can give rise to specialized cell types. In 2004, this speculation led to the discovery of the third type of dental stem cells which was referred to as PDLSCs. 9

PDLSCs have a multilineage differentiation potential. They were able to undergo osteogenic, adipogenic and chondrogenic differentiation when they were cultured with the appropriate inductive medium. 9,21

Dental Follicle Precursor Cells (DFPCs)

The dental follicle (DF), is a loose connective tissue of an ectomesenchymal origin and it is present as a sac surrounding the unerupted tooth 22. During tooth development it has been found that DF plays an important role in the eruption process by controlling the osteoclastogenesis and osteogenesis needed for eruption. 23,24 It is also believed that DF differentiates into the periodontium as the tooth is erupting and becomes visible in the oral cavity. 22,25 As the periodontium is composed of several cell types, it is reasonable to propose the presence of stem cells within the dental follicle which are able to give rise to the periodontium.

Stem Cells of Apical Papilla (SCAPs)
During tooth development, the dental papilla evolves into the dental pulp, and contributes to the development of the root. The apical part of the dental papilla is loosely attached to the developing root, and it is separated from the differentiated pulp tissue by a cell rich zone. It contains less blood vessels and cellular components than the pulp tissue and the separating cell rich zone. 3,26

Role of Dental Stem Cells in Regenerative Medicine
The dynamic features of isolated dental stem cells revealed much potential for their use in regenerative medicine and tissue engineering.
1) Dental Pulp Regeneration
Since the discovery and isolation of the different types of dental stem cells, there have been many attempts to use them in the regeneration of the dental pulp tissue. Using a tooth slice model, pulp-like tissue was engineered using SHEDs seeded onto synthetic biodegradable scaffolds. SHEDs were able to differentiate into odontoblast-like cells, and also endothelial-like cells. 27

2) Bio-Root Engineering
Sonoyama et al. demonstrated the use of combined mesenchymal stem cell populations for root/periodontal tissue regeneration. They loaded root shaped hydroxyapatite/tricalcium phosphate (HA/TCP) block with swine SCAPs. They then coated the HA/TCP block with gelfoam containing swine PDLSCs and inserted the block in the central incisor socket of swine. Three months post-implantation, histological and computerized tomography scan revealed a HA/SCAP-gelfoam/PDLSC structure growing inside the socket with mineralized root-like tissue formation and periodontal ligament space. These findings suggest the ability of combined autologous SCAP/PDLSCs generating a bio-root, which can be an alternative to dental implants in replacing missing teeth. 10

3) Neural Regeneration
Cranial neural crest (CNC) cells represent an ideal source for neuronal differentiation and regeneration. 28 The migrating CNC cells contribute to the formation of dental papilla, dental pulp, PDL and other tissues in the tooth and mandible. 29 Therefore, it is reasonable to consider that the different types of dental stem cells are of CNC origin. Different dental stem cells expressed neural and neural crest markers with or without induction. 8,10,12 In vitro and in vivo studies of SHEDs demonstrated that these cell populations were able to differentiate into neurons based on cellular morphology and the expression of early neuronal markers. 8,30

4) Cardiac Repair
It was found that DPSCs can help cardiac repair after myocardial infarction. In an experimental model of acute myocardial infarction, the left coronary artery was ligated in nude rats. Then DPSCs were transplanted to the border of the infarction zone. Four weeks after transplantation, evidence of cardiac repair was noted by improved cardiac function, increase in the number of vessels and a reduction in infarct size. The cardiac repair occurred in the absence of any evidence of DPSCs differentiation into cardiac or smooth muscle cells.

The discovery of a dental source for stem cells could very well prove to be a milestone in the regenerative medicine. The minimal intervention required to obtain dental soft tissues within the oral cavity provides an advantage and may help avoid rejection by recipients. Advances in the isolation and understanding of dental stem cells have opened areas of research into the possibility to ‘regrow’ lost dental tissues. This may not only prevent tooth loss but also fundamentally change the concept and definition of a dental caregiver.

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#1 Guest 2013-02-18 10:11
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