STEM CELLS FOR PERIODONTAL REGENERATION
Pejcic A1,*, Kojovic D1, Mirkovic D2, Minic I3
*Corresponding Author: Ana Pejcic, DDM, PhD, Periodontology and Oral Medicine, Medical Faculty, University
of Nis, dr Z. Djindjic 81 Blvd, 18000 Nis, Serbia; Tel.: +381-64-25-72-178; dranapejcic@ hotmail.com
page: 7
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INTRODUCTION
Periodontitis is an inflammatory disease which
manifests clinically as loss of supporting tissues
including periodontal ligament and alveolar bone,
which potentially leads to tooth loss. In the world
population, around 35.0% of adults suffer from
moderate form of periodontitis, while 15.0% are affected
by a severe generalized form of perio-dontitis
at some stage in their lives [1]. The significant burden
of periodontal disease and its impact on general
health and patient quality of life point to the need
for more effective management of the condition [2].
Once damaged, the periodontium has a limited capacity
for regeneration. During the early phases of the
disease, some minor regeneration of the periodontium
may be seen. However, once periodontitis becomes
established, only therapeutic intervention has the
potential to induce regeneration [3]. Procedures to
achieve periodontal regeneration have included root
surface conditioning, bone graft placement, guided
tissue regeneration and growth factor application.
However, current regenerative procedures have limitations
in attaining complete and predicable regeneration,
especially in advanced periodontal defects [4].
For successful perio-dontal regeneration, formation
of a functional epithelial seal, insertion of new connective
tissue fibers into the root, reformation of a
new acellular cementum on the tooth sur-face and
restoration of alveolar bone height are required. The
complex events associated with periodontal regeneration
involve recruitment of locally-derived progenitor
cells that can differentiate into periodontal
ligament cells, mineral-forming cementoblasts, or
bone-forming osteoblasts [5,6].
Advances in stem cell biology and regenerative
medicine have presented opportunities for tissue engineering and gene-based approaches in periodontal
therapy [7,8]. These new approaches, offers interesting
alternatives to existing therapies for the repair and
regeneration of the periodontium.
We here review current understanding of stem
cells, their potential application in regenerative periodontal
therapy, and discuss the challenges of translating
stem cell research into clinical practice.
The Types of Stem Cells. Stem cells are the
foundation cells for every organ and tissue in the
body, including the periodontium [9]. They have
two defining characteristics: the ability for indefinite
self-renewal to give rise to more stem cells, and
the ability to differentiate into a variety of specialized
daughter cells to perform specific functions
[10]. When a stem cell divides asymmetrically, one
daughter cell retains the stem cell characteristics,
while the other is destined for specialization under
specific conditions [11]. A pluripotent stem cell can
differentiate into all cell types of the body, whereas
a multipotent stem cell can differentiate into many
different cell types.
The two types of stem cells – embryonic and
adult – are classified according to their origin and differentiation
potential. Human embryonic stem cells
are pluripotential and differentiate into all types of
specialized body cells [12]. Their use for clinical
therapy is a relatively new endeavor. Adult, or tissuespecific,
stem cells are found in the majority of fetal
and adult tissues. They are derived from tissues that
continually replenish themselves (peripheral blood,
dermis and gastrointestinal epithelium) [13]. They
are multipotential [14] and are thought to function
by replacing cells that are injured or loss. Their most
common source is the bone marrow (hematopoietic
stem cells) or bone marrow stromal cells (mesenchymal
stromal stem cells). These last can be potential
candidates for perio-dontal regeneration [15]. They
can differentiate into endothelial, perivascular, neural,
bone or muscle cells [16].
Mesenchymal stem cells can effectively regenerate
destroyed periodontal tissue. Those derived from
bone marrow or adipose tissue have been used in
experimental animal models. They have been shown
to form cementum, periodontal ligament and alveolar
bone in vivo after implantation into periodontal
defects in beagle dogs [17]. Mesenchymal stem cells
have also been identified in adipose tissue [18]. As
adipose tissue requires less-invasive methods and is
abundant, it is very appealing as a source of cells for
regenerative periodontal therapy.
Stem Cells in Dental and Periodontal Tissues.
The identification and manipulation of stem cells
has greatly advanced regenerative medicine and has
contributed to development of tissue engineeringbased
clinical therapies [19]. One of the critical requirements
for a tissue engineering approach is the
delivery of ex vivo expanded progenitor populations
or the mobilization of endogenous progenitor cells
capable of proliferating and differentiating into the
required tissues.
The periodontal ligament, a highly fibrous and
vascular tissue, has one of the highest turnover rates
in the body. Its cells include cementoblasts, osteoblasts,
fibroblasts, endothelial and epithelial cells, and
a population of “progenitor cells” [20] that exhibit
some of the features and characteristics of mesenchymal
stem cells.
The first human dental stem cells, isolated from
dental pulps tissue of extracted third-molar teeth,
were characterized relative to bone marrow mesenchymal
stem cells [21]. Periodontal ligament stem
cells have been shown to give rise to adherent clonogenic
clusters resembling fibroblasts that may
develop into adipocytes, osteoblast-like cells and
cementoblast-like cells in vitro, and into cementumlike
and periodontal ligament-like tissues in vivo [22].
They are similar to stem cells of dental pulp, and to
bone marrow mesenchymal stem cells.
Mesenchymal progenitor cells, isolated from
the dental follicle of human third-molar teeth [23]
can generate perio-dontal ligament-like tissue [24],
implying that they may be a useful for regenerative
periodontal therapy. However, it remains to be determined
which source of dental mesen-chymal stem
cells is most suitable for regenerative therapy. This
prospect represents a step forward in development
of more predictable biologically-based therapy for
the perio-dontium.
Stem Cells in Periodontal Regeneration. In
dentistry, the identification of mesenchymal stem
cell-like populations has presented possibilities for
the application of tissue engineering in the development
of novel strategies for regenerative periodontal
therapy. One approach to perio-dontal regeneration
involves incorporation of progenitor cells in a periodontal
defect [25]. Tissue-engineering strategies
have been applied to reconstruct damaged perio-dontium [26]. Autologous bone marrow mesenchymal
and adipose-derived stem cells do regenerate alveolar
bone and periodontal ligament-like structures after
transplantation [27]. An ideal source may be human
adult dermal fibro-blasts reprogrammed to pluripotency
and to production of enough cells for regenerative
periodontal therapy [28].
These results from animal models are paving
the way for human regenerative periodontal therapy
[29,30]. They demonstrate the feasibility and potential
of dental and non dental stem cells for functional
periodontal and tooth regeneration. They also indicate
that periodontal ligament can be an efficient
autologous source of stem cells with a high expansion
capacity and ability to differentiate into osteogenic
cells that can colonize and produce a biocom-patible
scaffold [31,32].
Differentiation Potential of Periodontal
Ligament Stem Cells. Previous studies have demonstrated
that periodontal ligament stem cells can
build a typical cementum-periodontal ligament-like
structure [33]. Expanded perio-dontal stem cells
are heterogeneous in morphological characteristics,
differentiation potential and proliferative capacities
[34].
Periodontal Regeneration. A main goal of
periodontal therapy is regeneration of the affected
tissues to their original architecture and function.
Polypeptide growth factors such as epidermal growth
factor, fibroblast growth factor, platelet-derived
growth factor and bone morpho-genetic proteins [6]
have been used to facilitate periodontal regeneration.
The clinical results have been encouraging and these
factors seem capable of promoting regeneration of
periodontal tissues, albeit not in a completely predictable
or consistent manner [35].
The successful use hematopoietic bone marrow
reconstitution in cancer patients has led to investigation
of other stem cells as potential therapy for other
diseases and congenital defects [36]. The presence
of different mesenchy-mal stem cells in dental or
craniofacial tissues invites clinical investigations into
regeneration of orofacial and perio-dontal regions
[37]. Cells with characteristics of putative mesenchymal
stem cells were found in regenerating periodontal
tissues [38].
Biological Challenges. Despite biological evidence
that periodontal regeneration can occur in humans,
complete and predictable regeneration remains
an exclusive clinical goal and the molecular processes
that underlie stem cell proliferation and differentiation
are largely unknown. While the use of stem
cells can minimize the processing time compared
with somatic cells, posible karyotypic instability and
gene mutations of the cells after prolonged culture
can limit their usefulness. Immune rejection after
administration, oncogenic properties of stem cells
and functional integration on transplanted tissues
into the host [39] are significant challenges. Use of
autologous stem cells to overcome immune rejection
[19] is a possible solution.
Restoration of tissues destroyed by periodontitis
to their original form and function has been a
long-standing goal of periodontal therapy. Current
available regenerative therapies are poor clinical
predictability and there is a need for novel regenerative
technologies to be developed based on contemporary
understanding. A number of studies have
reported that stem cells, in conjunction with different
physical matrices and growth factors, have the
capacity to regenerate periodontal tissues in vivo.
In spite of these significant advances there are still
numerous biological, technical and clinical hurdles
to be overcome. It is not clear if human stem-cell
derivatives can integrate into the recipient tissue and
fulfill the specific functions of lost or injured tissue
[40]. Demonstration that stem cells develop into
stable cells and display the characteristics and functions
of normal host cells following their transplantation
is essential. It is auspicious that Ding et al.
[30] have elevated full-thickness periodontal flaps
and applied a mesenchymal-stem-cell and plateletrich
plasma to the root surface and adjacent defect
space resulting in a 4 mm reduction of periodontal
pocket depths and disappearance of bleeding and
tooth mobility. In addition, radiographic assessment
showed that the bone defect had been reduced in
depth. Thus, mesenchymal stem cells may prove
useful for periodontal tissue regeneration, treatment
of esthetically sensitive sites, and reduction of patient
morbidity.
With the first reports of adult human stem cells
populations residing in the periodontal ligament, the
next phase will be to determine the clinical utility of
these cells. Thus, future research efforts might be
focused on the potential use of this cell population
in tissue engineering and in their maintenance and
differentiation in vitro and in vivo.
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