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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

Keywords:
Dental
Stem
cells,
Regenerative Dentistry, Stem cells and
Dentistry,
Stem
Cells,
pulp
regeneration, Regeneration therapy.

Introduction
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: rizsk123@gmail.com
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.

Human dental tissue have limited potentials


to regenerate but the discovery of dental
stem cells have developed new and
surprising
scenario
in
regenerative
[1]
dentistry . 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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23
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
Stem Cells

Mesenchymal

Many researchers studied bone marrowderived mesenchymal stem cells and


demonstrated their therapeutic effect. In the
last decade, these cells have proven to be
successful to treat leukemia [34]. Nonhematopoietic
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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24
(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 biotooth 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

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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
(PDLSCS)

Ligament

Stem

Cells

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
[70,
71].
extracted
teeth
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
[47]
periodontium
. Kawanabe et al. identified
highly proliferating stem cells in human
[75].
periodontal
ligaments
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
(SCAP)

from

Apical

Papilla

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
(DFPCs)

Precursor

Cells

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)

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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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