Dental Stem Cells and Their Potential Role in Regenerative Medicine

Journal of Medical Sciences (2011); 4(2): 53-61

Review Article

53

Open Access

Dental Stem Cells and Their Potential Role in Regenerative Medicine

Mohamed Jamal1,2, Sami Chogle1, Harold Goodis1 and Sherif M. Karam2 1Boston University Institute of Dental Research and Education, Dubai

2Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates

Abstract:

Advances have been made in identifying dental stem

cells and their differentiation potential. Five different types

of dental stem cells have been isolated from dental soft

tissues: dental pulp, apical papilla, dental follicle and

periodontal ligament. The characteristic features of these

cells have been explored. They express various arrays of

biomarkers including those specific for mesenchymal

and/or embryonic stem cells. In vitro and in vivo studies

have revealed that these stem cells varied in their prolif-

eration and differentiation potential. Recent studies have

demonstrated their wide range of plasticity and their po-

tential 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.

Correspondence

SHERIF M. KARAM

Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al-Ain, UAE Tel: +971-3-7137493 Fax: +971-3-7672033 E-mail: [email protected]

Keywords: Dental stem cell, differentiation, regeneration, tissue engineering.

Introduction 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 ad-vantage 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 (Fig. 1).5 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 en-doderm.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 dif-ferent soft tissues of the tooth. The tooth is mainly made of hard tissues which are con-nected to soft tissues. The hard tissues include the dentin which is covered by enamel in the

Journal of Medical Sciences (2011); 4(2) JAMAL et al.

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crown and cementum in the root (Fig. 2). The

dentin encloses the dental pulp which is a richly innervated, highly vascularized soft (loose connective) tissue. The tooth is at-tached to its bony socket by another kind of soft (dense connective) tissue, the periodontal ligament (PDL).

In 2000, Gronthos et al. isolated the first MSC-like cells from the human dental pulp.7 Subse-quently, four more types of MSC-like cells have

been isolated from dental tissues: pulp of exfo-liated deciduous teeth8, PDL9, apical papilla10 and dental follicle.11 In this review, information available on these different types of dental stem cells and their potential use in regenera-tive medicine are summarized.

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

Fig. (1). Classification of human adult stem cells based on their origin or location. Stem cells can be catego-rized into two main types: germline and somatic which are found in different organs. Dental stem cells are mesenchymal in origin.

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DENTAL STEM CELL PROPERTIES Journal of Medical Sciences (2011); 4(2)

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are clonogenic in nature and can maintain their high proliferation rate even after exten-sive subculturing.7 There is no specific bio-marker to identify the DPSCs. However, DPSCs express several markers including the mesen-chymal and bone marrow stem cell markers, STRO-1 and CD146 as well as the embryonic stem cell marker, Oct4 (Table 1; complete list of markers available in reference 12).

Culturing DPSCs with various differentiation media demonstrated their dentinogenic, os-teogenic, adipogenic, neurogenic, chondro-genic and myogenic differentiation capabili-ties.12-14 Following their transplantation in ani-mal models, DPSCs were able to maintain their self renewal and to form pulp-like tissue, odon-toblast-like cells, ectopic dentin as well as re-parative dentin-like and bone-like tissues.7,12,15

The characteristic features and multilineage differentiation potential of DPSCs have estab-lished 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 iso-lated 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

Fig. (2). The structure of mature (A) and immature (B-D) teeth.

A. Illustration of mature fully erupted tooth showing the enamel (1) covering the dentin (2) in the crown. The cementum (3) covers dentin in the root. The dental pulp (4) is covered by the dentin. The periodontal liga-ment (5) connects cementum with the alveolar bone (6). The white arrow represents a mature closed root.

B. Illustration of immature partially erupted tooth exhibiting the dental follicle (7) and the apical papilla (8). The yellow arrow represents an immature open root.

C. A radiograph showing a mature fully erupted tooth (white arrow), an immature partially erupted tooth with an open root (yellow arrow) and an immature unerupted tooth with dental follicle (red arrow).

D. A radiograph showing an erupted primary (red star) and growing permanent (white star) teeth.

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and a higher number of colony forming cells than DPSCs.7,8

SHEDs were found to express early mesenchy-mal stem cell markers (STRO-1 and CD146).8 In addition, embryonic stem cell markers such as Oct4, Nanog, stage-specific embryonic anti-gens (SSEA-3, SSEA-4), and tumor recognition antigens (TRA-1-60 and TRA-1-81) were found to be expressed by SHEDs.16

The multilineage differentiation potential of SHEDs was demonstrated under different in-ductive conditions. SHEDs showed the capac-ity to undergo osteogenic and adipogenic differentiation. When SHEDs were cultured with neurogenic inductive media, they formed sphere-like clusters and changed their fibro-blastic morphology into cells with multiple cy-toplasmic processes. Under the same neuro-genic culturing condition, SHEDs expressed dif-ferent neuronal and glial cell markers such as nestin.8 The expression of these markers may suggest a neural crest origin of these cells.

When SHEDs were transplanted into immuno-compromised mice, dentin-like structure was formed, and was immunoreactive to dentin

specific sialophosphoprotein antibody. Odon-toblast-like cells were found to be associated with this regenerated dentin structure, which indicate the odontogenic differentiation po-tential of SHEDs. However, unlike DPSCs, SHEDs did not form a dentin-pulp complex after in vivo transplantation. This indicates that SHEDs have different odontogenic differentiation po-tential than DPSCs.8 In regard to the os-teogenic differentiation potential, it was inter-esting to find that SHEDs, unlike DPSCs, were not able to differentiate into osteoblast or os-teocyte, but were able to induce the host cells to undergo osteogenic differentiation. This is another difference in the differentiation poten-tial of SHEDs and DPSCs which demonstrates that SHEDs, unlike DPSCs, have an osteoinduc-tive potential rather than a differentiation po-tential.8 Due to their higher proliferation rate, unlike DPSCs, and their odontogenic and os-

Table 1. Summary of Dental Stem Cell Properties

DPSC7 SHED8 PDLSC9 DFPC11 SCAP10

Source Dental Pulp Dental Pulp‡ Periodontal ligament Dental Follicle Apical Dental Papilla

Differentiation potential (In vitro and in vivo)

Adipogenic + + + + +

Chondrogenic + + + + ND

Myogenic + + ND + ND

Neurogenic + + + + +

Odontogenic + + + + +

Osteogenic + + + + +

Stem cell markers

CD146 + + + + +

Nanog +

Nestin + +* + +

Notch-1 +

OCT4 + +

STRO-1 + + + + + ‡ From primary tooth +* After induction ND Not determined


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teogenic differentiation potential, SHEDs ap-pear to be distinct from the DPSCs and might indicate a more immature form than DPSCs.

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 Heteroge-neity 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 were isolated using the same method-ology for DPSCs and SHED, but this time, the tissue used was from the separated PDL of the roots of impacted human third molar. The iso-lated cells were fibroblast-like and clonogenic, but showed a high rate of proliferation, com-parable to that of the DPSCs but more prolific than the bone marrow MSCs.9,21

PDLSCs were found to express STRO-1, CD146 and scleraxis (tendon specific transcription factor). Scleraxis is expressed at a higher level in PDLSCs than in DPSCs and bone marrow MSCs. This finding was expected as the PDL and tendon exhibit similar structural contents of dense collagen fibers and similar ability to absorb mechanical stress during normal physiological activity.9

PDLSCs have a multilineage differentiation po-tential. They were able to undergo osteogenic, adipogenic and chondrogenic differentiation when they were cultured with the appropriate inductive medium.9,21 When PDLSCs were transplanted into immunocompromised mice, a typical cementum-PDL structure was formed, which was not produced in the case of DPSCs or bone marrow MSCs. The newly formed PDL-like tissue was composed of type I collagen and interestingly it was connected to the cementum in the same way Sharpey’s fi-

bers of the PDL attach to the cementum of the tooth.9

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 (Fig. 2).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 dif-ferentiates 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 perio-dontium.

In 2005, Morsczeck et al. were successfully able to isolate stem cells from the dental folli-cle of the human impacted third molar, using the same methodology of DPSCs isolation and culture.11 The cells were fibroblast-like and ex-pressed various markers, such as nestin and Notch-1.11

The potential of DFPCs to undergo osteogenic, adipogenic and neurogenic differentiation was demonstrated using in vitro studies.11, 26-28 When the neurogenic differentiation potential of DFPCs was compared with that of SHEDs, different neural cell marker expression patterns were revealed suggesting different neuronal differentiation potential.29 DFPCs were also able to differentiate and express cemen-toblast markers (cementum attachment pro-tein and cementum protein-23) after being induced with enamel matrix derivatives, or BMP-1 and BMP-7.30

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 (Fig. 2). The apical part of the dental papilla is loosely at-tached to the developing root, and it is sepa-rated from the differentiated pulp tissue by a


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cell rich zone. It contains less blood vessels and cellular components than the pulp tissue and the separating cell rich zone.3,31 In 2006, Sonoyama et al. isolated a new population of dental stem cells, and called them SCAPs.10 SCAPs are clonogenic fibroblast-like cells, but have a higher proliferation rate than DPSCs.10

As other dental stem cells, SCAPs express the early mesenchymal surface markers, STRO-1 and CD146. However, SCAPs also express CD24, which could be a unique marker for this cell population.10,31

The capacity of SCAPs to differentiate into functional dentinogenic cells has been verified by the same approaches as for the above-mentioned dental stem cells. SCAPs have the capacity to undergo osteogenic, adipogenic, chondrogenic and neurogenic differentiation, when they are cultured in the appropriate in-ductive media. As in the case of DPSCs, when SCAPs were transplanted into immunocom-promised mice in an appropriate carrier ma-trix, a typical dentin-pulp like structure was formed, with odontoblast-like cells.31

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 differ-ent types of dental stem cells, there have been many attempts to use them in the re-generation of the dental pulp tissue. Using a tooth slice model, pulp-like tissue was engi-neered using SHEDs seeded onto synthetic biodegradable scaffolds. SHEDs were able to differentiate into odontoblast-like cells, and also endothelial-like cells.32 In another study using the same tooth slice model, DPSCs were seeded on collagen scaffold supplemented with dentin matrix protein (DMP-1) and were able to regenerate pulp-like tissue.33 These findings suggest that SHED and DPSCs can be considered as reliable sources of stem cells for dental pulp tissue engineering and regenera-tion.

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/tri-calcium 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, his-tological 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 alter-native 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.34 The migrating CNC cells con-tribute to the formation of dental papilla, den-tal pulp, PDL and other tissues in the tooth and mandible.35 Therefore, it is reasonable to con-sider that the different types of dental stem cells are of CNC origin. Different dental stem cells expressed neural and neural crest mark-ers 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.8,36 Other studies on DPSCs, demonstrated that these cells responded to neuronal inductive conditions both in vitro and in vivo and ac-quired a neuronal morphology, and expressed neuronal-specific markers at both the gene and protein levels.12,37 They also exhibited the capacity to produce a sodium current consis-tent with functional neuronal cells when ex-posed to neuronal inductive media.38 In a re-cent study and using an animal model, it was found that avian trigeminal ganglion axons migrated toward the implanted DPSCs, and this was due to CXCL12 expression by the


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DPSCs. This expression pattern assisted in the homing of endogenous neural stem cells to the site of DPSCs transplantation. These find-ings provided an evidence that DPSCs might be able to induce neuroplasticity within a re-ceptive host nervous system.39 All these find

ings indicate that dental tissues represent an alternative, promising and less invasive stem cell source for neuronal regenerative-based therapy.

4) Cardiac Repair It was found that DPSCs can help cardiac re-pair after myocardial infarction. In an experi-mental 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, in-crease in the number of vessels and a reduc-tion in infarct size. The cardiac repair occurred in the absence of any evidence of DPSCs dif-ferentiation into cardiac or smooth muscle cells. This suggests that DPSCs induced cardiac repair due to its secretion of different growth factors and cytokines such as vascular endo-thelial growth factor, insulin-like growth factor-1 and -2 and stem cell factor, which helped in inducing angiogensis and cardiac regenera-tion at the infarction zone.40 Therefore, it seems that DPSCs have the potential to be used as a novel and alternative source for treatment of not only dental but also some other ischemic diseases.

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

and definition of a dental caregiver. The im-pact of this source of stem cells is even more far-reaching for the medical field. Current re-search is exploring the capability of the dental stem cells to differentiate into non-dental tis-sues such as cardiac muscle. Previously un-

treatable patients may now be improved by using stem cells harvested from their own teeth. The relative minimal intervention re-quired to obtain the cells and the absence of rejection issues may be the prime advantages to support such therapies in the near future. Although many studies have to be conducted before applying such therapeutic modalities, the dental stem cells represent a powerful tool which holds a significant potential for ad-vancement in the field of regenerative den-tistry and medicine.

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Dental Stem Cells and Their Potential Role in Regenerative Medicine

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