pulp tissue from primary teeth: a new source of stem cells

J Appl Oral Sci. 189
abstract
www.scielo.br/jaos
Pulp tissue from primary teeth: new source of
stem cells
Paloma Dias TELLES1
, Maria Aparecida de Andrade Moreira MACHADO2
, Vivien Thiemy SAKAI3
,
Jacques Eduardo NÖR4
1- DDS, PhD,Assistant Professor, Department of Community Dentistry and Pediatric Dentistry, Dental School, Federal University of Bahia, Salvador, BA, Brazil.
2- DDS, PhD, Professor, Department of Pediatric Dentistry, Orthodontics and Community Health, Bauru School of Dentistry , University of São Paulo, Bauru, SP, Brazil.
3- DDS, PhD, Assistant Professor, Dental School, Federal University of Alfenas, Alfenas, MG, Brazil.
4- DDS, PhD, Professor, Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry; Department of Biomedical Engineering, College
of Engineering, and Department of Otolaryngology, School of Medicine; University of Michigan, Ann Arbor, Michigan, USA.
Corresponding address: Profa
Dra
Paloma Dias Telles - Faculdade de Odontologia da Universidade Federal da Bahia - Departamento de Odontologia Social
e Pediátrica - Rua Araujo Pinho, 62, Canela - Salvador, BA - Brazil - 40110-150 - Phone/Fax: +55-71-3283-8975 - e-mail: p-telles@uol.com.br
Received: March 16, 2010 - Modification: May 10, 2010 - Accepted: September 15, 2010
SHED (stem cells from human exfoliated deciduous teeth) represent a population of
postnatal stem cells capable of extensive proliferation and multipotential differentiation.
Primary teeth may be an ideal source of postnatal stem cells to regenerate tooth structures
and bone, and possibly to treat neural tissue injury or degenerative diseases. SHED are
highly proliferative cells derived from an accessible tissue source, and therefore hold
potential for providing enough cells for clinical applications. In this review, we describe the
current knowledge about dental pulp stem cells and discuss tissue engineering approaches
that use SHED to replace irreversibly inflamed or necrotic pulps with a healthy and
functionally competent tissue that is capable of forming new dentin.
Key words: Tissue regeneration. Dental pulp. Tissue engineering. Endodontics.
Introduction
The history of research on adult stem cells began
about 40 years ago. In the sixties, researchers
discovered that bone marrow contains at least
two kinds of stem cells. One population, called
hematopoietic stem cells, forms all the types of
blood cells in the body. A second population, called
bone marrow stromal cells, was discovered few
years later. Stromal cells are a mixed population of
progenitor cells that generate bone, cartilage, fat,
and fibrous connective tissue2,4-7,16,43,45,48,52,57
. Today,
stem cell biology is one of the most fascinating
areas of sciences. However, like many other
expanding fields of scientific inquiry, research on
stem cells raises scientific questions as rapidly as
it generates new discoveries.
Postnatal stem cells have been isolated from
a variety of tissues including bone marrow, brain,
skin, hair follicles, skeletal muscle and dental pulp.
These cells are thought to possess great therapeutic
potential for repairing damaged and/or defective
tissues3-5,8,9,12-15,17,19,20,24,29,35,37,44,58
. It has been shown
that stem cells from human exfoliated deciduous
teeth (SHED) represent a population of postnatal
stem cells capable of extensive proliferation and
multipotential differentiation. The transition from
deciduous to permanent teeth is a very unique and
dynamic process in which the development and
eruption of permanent teeth synchronize with the
resorption of the roots of deciduous teeth. Exfoliated
deciduous tooth is similar in some ways to an
umbilical cord, containing stem cells that may offer
a unique postnatal stem cell source for potential
clinical applications1,10,39,56
. It has been demonstrated
that stem cells are present within the pulp tissue
not only of deciduous teeth, but also in permanent
teeth (dental pulp stem cells – DPSC), and in the
periodontal ligament (periodontal ligament stem
cells – PDLSC)2,3,7,13,16,19,20,26,28,40,44,51
. This manuscript
is designed to serve as a comprehensive synthesis
of our current knowledge of stem cells from human
exfoliated deciduous teeth and to describe the
current efforts on tissue engineering with the use
of SHED in order to replace irreversibly inflamed
or necrotic pulps due to dental caries by a healthy
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and functionally competent tissue.
Stem cells
Stem cell is a broad term used to describe a wide
variety of cells from varying sources. Stem cells can
be divided into two categories – embryonic and adult.
Embryonic stem cells are totipotent cells capable of
differentiation into virtually any cell type, as well as
being propagated indefinitely in an undifferentiated
state1,3,5,8,10,14,16-18,24,25,27,28,31-34,38,39,47,49,50,54
. Adult
stem cells are not totipotent, and they can be
further classified depending on their origin and
differentiation potencial3,14,19,26,31,35
. The use of
embryonic stem cells generates several ethical
concerns regarding the consumption of blastocystes.
This makes postnatal stem cells a more feasible
approach for translation into clinical practice.
Stem cells fascinate us from both theoretical and
practical viewpoints. Their defining characteristics
– extensive proliferative potential and ability to
give rise to one or more differentiated cell types –
are more common in early mammalian embryos.
However, embryonic cells loose these properties
as differentiation ensues and growth-promoting
signals decline. By adulthood, the few remaining
stem cells are dispersed and virtually invisible, but
the surviving adult stem cells achieve something
remarkable: they can operate as “steady state”
– that is, they can generate on average one
replacement stem cell and one tissue-specific cell
at each division with no apparent limit (Figure 1).
Stem cells differ from other kinds of cells in the
body. All stem cells, regardless of their source, have
three general properties: they are unspecialized;
they are capable of continuous self-renewal; and
they can give rise to specialized cell types.
Stem cells are unspecialized. One of the
fundamental properties of a stem cell is that it does
not have any tissue-specific structures that allow it
to perform specialized functions. A stem cell cannot
work with its neighbors to pump blood through
the body (like a heart muscle cell); it cannot carry
molecules of oxygen through the bloodstream (like
a nerve cell). However, unspecialized stem cells can
give rise to specialized cells, including heart muscle
cells, blood cells, or nerve cells1,7,9,17,24,30
.
Stem cells are capable of self-renewal. Unlike
muscle cells, blood cells, or nerve cells, which
do not normally replicate themselves, stem cells
may replicate many times. A starting population
of stem cells that proliferates for several months
in the laboratory can yield millions of cells. If the
resulting cells continue to be unspecialized, like the
parent stem cells, the cells are said to be capable
of long-term self-renewal.
Stem cells can give rise to specialized cells. When
unspecialized stem cells give rise to specialized cells,
the process is called differentiation. The internal
signals are controlled by proteins that regulate gene
expression and are called transcriptional factors.
The external signals for cell differentiation include
molecules secreted by other cells, physical contact
with neighboring cells, and molecules from the local
microenvironment.
Dental caries and pulp response
Dental caries is the most common chronic
disease affecting children in several countries.
Despite advances in oral health, dental and oral
diseases continue to plague children. Factors
contributing to an oral health decline include lack of
access to care, inadequate availability of preventive
measures and lack of knowledge regarding the
importance of oral health. Oral tissue infections and
associated nutritional deficits can lead to imbalances
in oral flora populations, eventually contributing to
compromised overall health and reduced quality of
children’s life6,7
. Over the last decades, biomedical
research has focused primarily on the understanding
of the mechanisms of biological functions in health
and disease. For example, our understanding of
the mechanisms of dental caries has advanced
tremendously5
. Dentists are faced every day with
the task of restoring tooth structure lost during the
progression of caries lesions. The development of
materials that allow for strong and stable bonding
to tooth structure, and the development of esthetic
materials that are resistant to wear and degradation
in the oral environment, has significantly enhanced
the long-term clinical outcomes of restorative
procedures. Nevertheless, dental clinicians know
that no material available today can mimic all the
physical, mechanical and esthetic properties of
enamel and dentin5,42
.
The field of tooth regeneration is one of the
ultimate goals of restoring the loss of natural teeth.
The ability to obtain and manipulate postnatal
tissue easily from individuals to generate biological
replacement tooth materials, such as dentin,
enamel, and periodontal ligament, or, even better,
to replace complete teeth of predetermined size and
shape, is extremely valuable1,8,10
. Small amounts of
reparative dentin can be induced to form in response
to subtle tooth injury and cementum also exhibits
limited regenerative capabilities. In contrast,
enamel exhibits no regenerative capacity because
progenitor dental epithelial cells that form enamel
loose this ability well before tooth eruption8,9
. The
high susceptibility of teeth to damage, combined
with non-regenerative nature of dental tissues,
emphasizes the need for regenerative tooth
therapies in children and adults4,10,30,41,55
.
In pathological conditions, such as mild carious
dentin lesions, odontoblastic activity is stimulated
to produce reactionary dentin. Severe carious
lesions or deep cavity preparation may lead to local
Pulp tissue from primary teeth: new source of stem cells
2011;19(3):189-194

odontoblastic death. However, undifferentiated
cells attracted to the injury site can differentiate
into odontoblast-like cells and secrete a reparative
dentin matrix. Several lines of evidence suggest
the presence of progenitor or postnatal stem
cells in the pulp capable of differentiation into
odontoblast-like cells and secretion of reparative
dentin in vitro11,12
. Odontoblast cells are post-mitotic
and are responsible for the secretion of primary
dentin. Indeed, reparative dentin synthesis is a
complex biological process. It requires the presence
of progenitor cells, their proliferation, migration,
recruitment and activation at the injury site to
differentiate into odontoblast-like cells secreting
the hard protective reparative dentin. The dental
pulp is a highly vascularized tissue and pulp cavity
preparation results in a subsequent injury to
the pulp tissue including the blood vessels. It is
recognized that injured endothelial cells release
chemotactic factors and signaling molecules to
initiate the inflammatory process and express
adhesion molecules necessary for the recruitment of
inflammatory and progenitor cells for initiating the
healing process14,15
. The presence of inflammation,
which will be exacerbated by bacterial infection, is
well recognized as a moderator of regeneration and
will probably inhibit regenerative processes as long
as it is maintained16,18
.
The concept of migration of stem cells to
the site of injury for differentiation into a new
generation of odontoblast-like cells is very important
event for cell recruitment during regeneration
when the vitality of the primary odontoblasts
is compromised17,19,20
. It is unclear whether
this reflects a direct effect on the stem cells for
regeneration or the molecular signaling processes
responsible for their differentiation. Nevertheless,
the presence of inflammation will compromise
stem cell recruitment and differentiation during
regeneration22,23
. An understanding that local
angiogenesis is a physiologic event during healing
at all wound sites, including the dental pulp with
a remarkable importance of nutrition during the
healing process, and it may also increase the
opportunities for perivascular stem cells recruitment
during regeneration26
.
Dental pulp-derived cells are potentially a useful
alternative for cell replacement in the treatment of
tissues known to contain neural stem cells. It has
been demonstrated the first successful induction
of neural differentiation of rat dental pulp-derived
cells, particularly into a glial cell lineage. Successful
in vitro and in vivo differentiation of neural stem
cells obtained from bone marrow into neurons and/
or oligodendrocytes has been also reported38,39,48
.
The authors concluded that the existence of neural
stem cells in tissues other than the central nervous
system may represent a significant step toward
providing more diverse and multiple sources of
stem cells for regenerative medicine38
.
The understanding of pulp biology has improved
significantly in recent years. However, it is still
Figure 1- Diagram depicting the expected clinical applications of some stem cell research
Source: National Institute of Health. The promise of stem cell research [figure on the internet]. Bethesda: NIH; 2009 [cited 2010 May 03]. Available from: http://
alumnimagazine.uconn.edu/sprg2007/feature2.html
TELLES PD, MACHADO MAAM, SAKAI VT, NÖR JE
2011;19(3):189-194

not possible to state with certainty which cell
populations and which specific molecular signaling
pathways predominate during dental regeneration.
If pulpal stem cells are to be optimally harnessed for
dental regeneration, then strategies are required to
ensure their effective recruitment at sites of injury.
Whilst such recruitment does occur during natural
regeneration, it is a somewhat haphazard process
lacking in control. Directed recruitment of these
cells might be achieved through local application
of enriched cell populations, either by harvesting
cells from non-autologous teeth or autologous shed
deciduous primary teeth.
Dental pulp tissue engineering with the use
of SHED
Although conventional restorative materials,
such as amalgam, composite resin and glass
ionomer cement, have been proven effective
in the maintenance of teeth in the oral cavity,
they clearly present a limited lifespan, thus
requiring replacement over time. Additionally, a
significant percentage of treated teeth undergo
pulp inflammation and necrosis, requiring further
endodontic treatment and prosthetic reconstruction
or tooth extraction. Therefore, the development
of new techniques capable of regenerating lost
tooth structure would benefit the population
significantly13
.
Nowadays, tissue engineering, which corresponds
to a multidisciplinary science that brings together
biology, engineering and clinical sciences with
developing new tissues and organs42
, constitutes a
promise as a new method to repair congenital and/
or diseased teeth36,57
. Particularly, the main goal
of dental pulp tissue engineering is to replace the
inflamed or necrotic pulp by a healthy and functional
tissue, capable of forming new dentin. This science
is based on principles in which undifferentiated
cells placed into biocompatible scaffolds respond
to specific signals that induce their proliferation,
migration and differentiation into specialized cell
lineages.
Common tissue engineering involves the seeding
of appropriate cells in biodegradable scaffolds
built with desirable mechanical features and the
stimulation of cell growth and differentiation
in vitro. When this set is implanted in vivo, it
may undergo remodeling and maturation into a
complete functional tissue36,57
. Therefore, dental
pulp tissue engineering may be the first step
toward dentin regeneration in necrotic teeth, as
well as an alternative to conventional endodontic
treatment21
, with the advantage of restoring tooth
vitality. Hence, the identification of appropriate
cells, the development of conductive scaffolds
and the understanding of morphogenetic signaling
required to induce cells to regenerate lost tissues
are mandatory42,43,53,59
.
Stem cells can be induced to differentiate into
a specific phenotype through the manipulation
of cell culture conditions. It is possible to control
or restrict available differentiation pathways and
selectively generate enriched cultures with a
particular phenotype. These manipulations include
cell stimuli with specific cytokines, growth factors,
amino acids, other proteins and active ions, and
co-culture with a specific cell type or tissue46
.
In vivo evidence for pulp cells being capable of
generating a dentin-pulp-like complex have been
demonstrated by Gronthos, et al.18
(2000) and
Miura, et al.39
(2003) who transplanted DPSC and
SHED, respectively, mixed with hydroxyapatite/
tricalcium phosphate into immunocompromised
mice. Within 6 weeks, a dentin-like structure
lined with odontoblast-like cells that surrounded
a pulp-like interstitial tissue and had their process
penetrating into tubular structures was observed.
Moreover, collagen fibers oriented perpendicularly
to the odontoblast layer within the dentin, which
is characteristic of primary dentin. Dentin-like
material formed in the implants had a mineralized
globular aspect, compatible with human dentin
structure. In addition, odontoblast-like cells and
the remaining pulp cells were from the donor18,39
.
When DPSC were seeded onto human dentin
surface and implanted into immunocompromised
mice, scattered reparative dentin-like structure was
deposited on the dentin surface4
.
Cordeiro, et al.11
(2008) evaluated morphologic
characteristics of the tissue formed when SHED
seeded in biodegradable scaffolds prepared
within human tooth slices were transplanted
into immunodeficient mice. The resulting tissue
presented architecture and cellularity that closely
resemble those of a physiologic dental pulp.
Ultrastructural analysis with transmission electron
microscopy and immunohistochemistry for dentin
sialoprotein suggested that SHED differentiated
into odontoblast-like cells in vivo. Notably, SHED
also differentiated into endothelial-like cells, as
demonstrated by B-galactosidase staining of cells
lining the walls of blood-containing vessels in tissues
engineered with SHED stably transduced with LacZ.
Using the same experimental model, Sakai,
et al.48
(2010) tested the hypothesis that SHED
differentiate into functional odontoblasts and
endothelial cells. SHED differentiated into functional
odontoblasts that generated new dentin, as
determined by tetracycline staining and confocal
microscopy. These cells also differentiated into
vascular endothelial cells, as determined by
B-galactosidase staining of LacZ-tagged SHED. In
vitro, vascular endothelial growth factor (VEGF)
induced SHED to express VEGFR2, CD31, and VE-
Cadherin (markers of endothelium) and organize
2011;19(3):189-194

into capillary-like sprouts. VEGF induced ERK and
AKT phosphorylation (indicative of differentiation),
while inhibiting phosphorylation of STAT3 (indicative
of stemness).
We are at an exciting point of a new era of
restorative dentistry harnessing the biological
activity of the dental tissues to facilitate wound
healing and tissue regeneration. There is still much
to learn of the nature, potentiality and behavior
of dental stem cells, but the opportunities for
their exploitation in dental tissue regeneration are
immense and will lead to significant benefits for
the management of the effects of dental disease44
.
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