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INTERNATIONAL DENTAL JOURNAL OF STUDENTS RESEARCH| Feb 2013-May 2013| Volume 1| Issue 4

REVIEW ARTICLE

Therapeutic Potential of Stem cells in Regenerative

Dentistry; a Review of Literature

Rizwan Abdul Rasheed Shaikh1

1Intern, Government Dental College & Hospital, Nagpur (Maharashtra State), INDIA

Corresponding Author

Rizwan Abdul Rasheed Shaikh, Room no-105, First Floor, Boys Dental Hostel, Govt. Medical College Campus, Medical Square, Nagpur PIN - 440 008 Email ID: [email protected] Contact No. (+91)9561101768

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Abstract The discovery of stem cells has developed

new but strange possibilities in the

regeneration of different tissue and organs.

Presently, research works and studies to

know potential and capabilities of stem cells

and their use in dentistry are becoming an

interesting topic. In a few years lots of

studies and demonstrations have been

carried out which show that stem cells and

tissue engineering are giving rise to a

separate branch named Regenerative Dentistry that will have its own position in future dental clinical practice. This short

review discusses the therapeutic potential of

stem cells in regenerative dentistry as seen

in studies and demonstrations carried out by

different workers.

Keywords: Dental Stem cells,

Regenerative Dentistry, Stem cells and

Dentistry, Stem Cells, pulp

regeneration, Regeneration therapy.

Introduction Human dental tissue have limited potentials

to regenerate but the discovery of dental

stem cells have developed new and

surprising scenario in regenerative

dentistry[1]. Stem cells are clonogenic cells

having capabilities of self renewal and

multi-lineage differentiation [2]. Topic of

Stem cells became an interesting topic in the

field of Dentistry to know their

characteristic features and potentials of

differentiation. Tissue engineering is the

branch that brings biology, bio-engineering,

clinical sciences and biotechnology together

for the purpose of generating new tissues

and organs [3]. Since last few decades,

Scientists have started to search the

potential applications of stem cells for the

repair and regeneration of dental and

dentofacial structures. Studies show the role

of stem cell and guided tissue regeneration

in periodontal treatment [4-6], in making of

Bio-tooth [7-18], in regenerating pulp like

tissue for regenerative endodontics [19, 20], in

dental implantology[21] and in regeneration

of craniofacial structure [1, 22, 23]. Literature

increasingly clears that conceptual approach

to therapy, named regenerative dentistry, will surely have its own position in the

future clinical practice of dentistry. This

short review discusses the potentials of stem

cells in newly emerged branch regenerative dentistry.

Stem Cells in Regenerative Dentistry Researchers define stem cells as the

clonogenic cells with the capability of self

renewal and multi-lineage differentiation

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and also have the capabilities of generating

complex tissues and various organs [2, 24].

Stem cells were discovered on November 5,

1998 by workers at the University of

Wisconsin (UWMadison) and Johns Hopkins University (JHU). Embryonic stem

cells and postnatal stem cells are two types

of stem cells [2, 25-28]. During the process of

embryo development, at early stages,

embryonic stem cells are found in inner cells

of blastocyst [29]. Embryonic stem cells are

the main source of cells in regenerative

therapies because these cells have potential

of self-renewal and capability to generate

new tissues and organs. Embryonic stem

cells are totipotent , however due to legal

and ethical issues it is not feasible to use

embryonic stem cells in the laboratory and

clinics [30-32]. Post-natal stem cells can be

isolated from various tissues such as bone

marrow, neural tissue, skin, dental pulp,

and the periodontal ligaments [2]. Postnatal

stem cells also have the capabilities of self

renewal, however if we compare multipotent

postnatal stem cells with totipotent

embryonic stem cells then it is found that

postnatal stem cells have very limited

potential of differentiation into other types

of cells[1]. Main advantage of postnatal stem

cells is minimum risk of immune rejection

during tissue transplantation. Secondly,

these cells can be taken from donor

individuals at any stage of their life [33].

Non-Hematopoietic Mesenchymal Stem Cells Many researchers studied bone marrow-

derived mesenchymal stem cells and

demonstrated their therapeutic effect. In the

last decade, these cells have proven to be

successful to treat leukemia [34]. Non-

hematopoietic bone marrow-derived

mesenchymal stem cells are also known as

BMSCs-bone marrow stromal cells [35]. Mesenchymal stem cells have the potential

to differentiate into osteoblasts (bone

forming cells), chondrocytes (cartilage

forming cells) or retinal cells [36-39]. Many

researchers demonstrated therapies

combining non dental mesenchymal stem

cells and dental mesenchymal stem cells [19,

32, 40, 41]. A new study demonstrated that

enamel matrix proteins have positive effect

on differentiation BMSCs into cementoblasts

(cementum forming cells) [42]. A recent case

by Yamada Y et al. (2006) presented a

patient with periodontitis, demonstrated the

use of MSCs in combination with platelet

rich plasma resulting in a reduction of

probing depths by 4mm with a 4mm gain in

clinical attachment level with disappearance

of bleeding and mobility of tooth [43]. This

demonstration proved that MSCs can

differentiate themselves into periodontal

tissue resulting in increase tooth support by

gain in clinical attachment and hence

decrease in mobility of tooth. So, it can be

thought that in future stem cell will be a

successful treatment to disappear or reduce

mobility of human tooth.

The first layer of human tooth is made up of

enamel, which is toughest structure of

human body and this enamel is formed by

ameloblast cells. Hu et al. demonstrated that

bone marrow-derived cells can be

differentiated into ameloblast (enamel

forming) like cells [44]. After this experiment

Lesot and colleagues cultured a combination

of murine bone marrow cells, dental

epithelial cells and dental mesenchymal cells.

Morphological changes were observed in

BMSCs and ameloblast specific markers

amelogenin and ameloblastin were found in

these morphologically changed cells [44]. This

demonstration gives an inference that

BMSCs can be very well programmed to

differentiate into ameloblast like cells [44]. It

indicates that in future it is possible to treat

dental diseases related to ameloblast cells

and enamel by using stem cells. All these

researches and demonstrations indicate

potential possibilities for regenerative

dentistry.

Dental Stem Cells In recent studies it has been demonstrated

that stem cells are present in various dental

tissues. In the pulp tissue of deciduous teeth

stem cells are present termed as Stem Cells

from Human Exfoliated Deciduous teeth

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(SHED) [28]. Dental Pulp Stem Cells (DPSCs)

is the name given to stem cells which are

present in Pulp tissue of human teeth [45]. In

the periodontal ligament researchers found

Periodontal Ligament Stem Cells (PDLSCs) [71]. While in dental papilla of wisdom teeth

Stem Cells from Apical Papilla (SCAP) is

present[46,47] and researchers termed stem cell

found in dental follicles of developing wisdom

teeth as Dental Follicle Precursor Cells (

DFPCs ) [48-50].

Dental Pulp Stem Cells (DPSCs) Adult dental pulp stem cells (DPSCs) were

discovered in wisdom teeth in 2000 [51].

Researchers isolated Dental

ectomesenchymal stem cells from the dental

pulp of the extracted wisdom teeth [33]. Same

as BMSC, DPSCs are colony forming plastic

adherent cells which display very similar

features [52]. Workers analyzed the profile of

gene expression of DPSCs and BMSCs which

show both cells are distinct precursor

populations but have a very similar gene

expression level [53]. In a chemically defined

culture medium, DPSCs can be differentiated

into smooth and skeletal muscle cells,

neurons, and cartilage and bone cells [54]. The

difference between BMSCs and DPSCs is

DPSCs can differentiate into odontoblast like

cells (dentin forming cells) [54]. To determine

the existence of DPSCs, previously developed

methodology was used for the isolation and

characterization of BMSCs and pluripotent

postnatal stem cells. DPSCs were

characterized as clonogenic and highly

proliferative stem cells [45]. S. Gronthos et al.

demonstrated that DPSCs possess all

qualities of stem cells [55].Various other

studies have revealed the potentials of

BMSCs in the treatment of certain diseases

and some conditions such as injury to the

spinal cord, muscular dystrophies, corneal

alterations, critical size bone defects and

systemic lupus erythematosus (SLE) [56-61]. It

is reported that DPSCs can differentiate into

endothelial cells which can make functional

blood carrying blood vessels [62, 63].

Human teeth have pulp chamber containing

pulp tissue, when this pulp tissue get infected

then it results in tooth pain. And to make

patient relieve from pain dentist perform root

canal treatment in which dentist remove pulp

from pulp chamber and replace with artificial

material like gutta purcha. In this process

patient get relive from pain but he loose

vitality of tooth. Stem cells derived from the

dental pulp can form pulp like tissue [19, 20].

Pulp-like tissue could be engineered in vitro,

using DPSCs seeded into synthetic matrices

made with polyglycolic acid [64, 65]. So as stem

cells can differentiate in pulp like tissue and

dentine pulp complex [7], in future it is

possible to replace infected pulp tissue of a

paining tooth with newly generated pulp like

tissue differentiated from stem cell and then

patient will be without pain along with his

vital teeth. Hence stem cell is topic of interest

in discussion for regenerative endodontics.

A big problem with dental implant is

improper osteointegration which lead to

implant failure but DPSCs have the ability to

form bone that is useful for the

osseointegration of dental implants coated

with hydroxyapatite crystals, and may give

good bone implant contact level [21].Hence

stem cell can increase the success rate of

dental implants. Ming Yan et al. suggested

that DPSCs are useful in reconstructing

dentin pulp complex and biotooth [7].

Human tooth is made up of enamel, dentin,

and cementum and pulp tissue. Enamel is

formed by ameloblast cells, dentin is made by

odntoblast cells, cementum is made by

cementoblast cells. Stem cell can differentiate

into all four tissues. Hence Ming Yan et al.

suggested that Bio-tooth can be made from

stem cells [7]. There are many studies which

demonstrate that reconstruction of the bio-

tooth is possible with dental stem cells [8-18]

Stem Cells of Human Exfoliated

Deciduous Teeth (SHEDS) Researchers have isolated ectomesenchymal

stem cells from the dental pulp tissue of

exfoliated incisors and they named them as

stem cells of human exfoliated deciduous teeth

(SHEDs) [66]. Studies suggest that SHEDs have

the ability of differentiation into odontoblasts,

neural cells and adipocytes [66]. Workers

25


compared SHEDs with DPSCs and found that

SHEDs have a higher rate of proliferation [28].

Same as DPSCs, SHEDs also have the

potential to form bone that might be useful

during osseointegration of dental implants

coated with hydroxyapatite crystal and may

result in good levels of bone implant contact [21].

Seo et al. have demonstrated that SHEDs have

the potential to repair calvarial defects in

immunocompromised mice [67]. Studies shows

that SHEDs and DPSCs both have the

potential of generating tissues that have

similar morphological and functional

characteristics resembling the human dental

pulp [62, 63, 68, 69].

Periodontal Ligament Stem Cells

(PDLSCS) The periodontium is a connective tissue organ

which attaches the teeth with the bones of

the jaws. It consists of periodontal ligament,

gingiva, cementum and alveolar bone [80].

Human PDLSCs have been successfully

isolated by scientists from the root of

extracted teeth [70, 71]. Researchers

demonstrated that if PDLSCs with

hydroxyapatite (HA) or tricalcium phosphate

(TCP) as a carrier are transplanted into

immunocompromised mice, then it can be

seen that PDLSCs have potentials of

regenerating typical cementum and

periodontal ligament like structure [4].

Studies suggest that if PDLSCs are

transplanted directly into periodontal defect

areas which are caused by periodontal

disease, it might be a viable therapeutic

approach [72, 73]. On the other hand, under in

vitro conditions, PDLSCs display a low

ability of differentiation into osteogenic tissue [70]. PDLSCs can get differentiated into cells

or tissues that are very similar to

periodontium [70]. Yi Liu, Ying Zheng, Ding et

al. demonstrated the role of autologous

PDLSCs to treat periodontitis in miniature

pig preclinical model and their study

indicated that a multilevel cellular or

biomaterial treatment may be an optimal

therapeutic approach for regeneration of

periodontal tissue [4].Researches have also

isolated PDLSCs from pigs and sheeps [47, 74].

They also suggest that PDLSCs can

successfully establish a functional

periodontium [47]. Kawanabe et al. identified

highly proliferating stem cells in human

periodontal ligaments [75]. These

demonstrations indicate that in future, tissue

of the periodontium made by stem cell can be

used as a treatment modality to replace the

diseased periodontium around teeth so as to

disappear mobility of tooth cause due to

diseased periodontium. Many more studies

are required for PDLSCs to provide new

insights useful for regenerative therapy in

dentistry.

Stem Cells from Apical Papilla

(SCAP) Researchers isolated stem cells from dental

apical papilla of wisdom teeth or incisors of

four months old mini pig termed as Stem Cells from apical papilla [46, 47]. Dental papilla is basically an embryonic tissue that

is responsible for the formation of dental pulp

and the crown. But SCAPs can only be

isolated at certain specific stages of the

development of tooth. As dental papilla

contain higher number of adult stem cells

than mature dental pulp, SCAPs have a

greater potential for regenerating dentin

than DPSCs [47]. SCAPs originate from an

embryonic-like tissue so they are less likely to

be differentiated than DPSCs. Study by

Sonoyama W et al. demonstrate formation of

dental connective tissue is induced by a

combination of SCAPs and PDLSCs [47]. But

this study is not clear as to which stem cells

were important for the synthesis of dental

connective tissue [47].

Dental Follicle Precursor Cells

(DFPCs) The dental follicle contains the precursors of

the periodontium so it plays a very important

role in development of tooth [48]. Cells of the

dental sac develop into a mature

periodontium which consists of alveolar bone,

cementum and the periodontal ligaments

(PDL) [48]. Research workers have observed

that Hertwigs epithelial root sheath (HERS)

26


disintegrates into epithelial fragments and

allows contact between surface of dentin and

dental follicle ectomesenchymal cells, and

here these cells differentiate into mature

cells of the periodontium [76,77]. This

demonstrate that dental follicles contain

progenitor cells which have the capability of

differentiating into cementum forming cells

(cementoblasts), osteoblasts of the alveolar

bone, and periodontal ligament fibroblasts.

Handa K (2002) isolated progenitor cells from

bovine dental follicles. In in vitro conditions

these cells formed clusters of spheroid like

cells and in in vivo conditions, cementum

matrix formation took place by these cultured

dental follicle cells [78]. The human dental

follicle is a tissue which belongs to tooth

germ, and after wisdom tooth extraction one

can isolate these cells very easily.

Ectomesenchymal cells are present in the

dental follicles; these cells are derived from

the neural crest [54]. Similar to BMSCs,

DFPCs are colony forming cells which are

also plastic adherent. Under in vitro

conditions these cells can be differentiated

into osteoblast like cells [54]. Different workers

suggest that like PDLSCs, DFPCs can also

differentiate to produce mineralized tissue [48,

49, 79]. Salles and colleagues completed a study

which confirms that human DFPCs have

properties like mesenchymal precursor cells

[50]. DFSCs can differentiate into

mesenchymal derived cells like

cementoblasts, adipocytes and chondrocytes [54].

Discussion and Conclusion In this article it can be seen the actual

progress in the research of dental stem cells

which makes it clear that in the future stem

cells will lead to development of an

alternative treatment for dental diseases like

periodontitis, cavities and pulp pathologies. It

is also clear that in future stem cells may be

of help to reconstruct the bone defects related

to dentoalveolar and craniofacial regions. It

might be possible to create an entire tooth to

replace missing teeth. Now it is so clear that

stem cells and tissue engineering can

definitely give rise to a new branch

Regenerative Dentistry by giving alternatives to root canal treatment (RCT)

and dental implants.

On the other hand, it is equally true that the

actual conditions to create the entire tooth

and tooth tissue in order to use it clinically

are not completely understood. More studies

and research works are required to use a

stem cell in making primordium tooth in vitro

for transplantation with the intention of

replacing a lost tooth. Hence the research

work on stem cells in regenerative dentistry

should be promoted to have its own position

in the clinical practice of dentistry in the

future.

Acknowledgements

I thank Dr. (Mrs.) W. A. Bhad, Head of

Department, Department of Orthodontics

and Dentofacial Orthopedics, Govt. Dental

College and Hospital, Nagpur for promoting

the undergraduate students in scientific and

research activities. I am also grateful to Dr.

Riyaz Ahemad, Post Graduate Student in

Oral and Maxillofacial Pathology and

Microbiology, Govt. Dental College and

Hospital, Nagpur for his valuable

suggestions and help, and for being a

constant source of inspiration during this

work

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Figure 1 Classification of Stem Cells in Regenerative Dentistry

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