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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_113_библиотеки_им_акад_М_И_Перельмана
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BMP-2
EMD
(a)
(b)
pSmad1/5/8
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bCatenin
GSK3a
GAPDH
Pre-dentine
Dentine
Enamel
15′ 30′ 1h 2 h
Figure1.2 Sequence of dentine formation –
(1)signalling from pre-
odontoblasts (DSPP, enamelysin and ameloblastin)
and deposition of a baseline collagen matrix;
(2)deposition of pre- dentine by the immature
odontoblasts, leading to signalling to ameloblasts;
(3) enamel deposition; (4)dentin (tubular
deposition). Both ameloblasts and odontoblasts
mature throughout the process.
Figure1.3 Western blotting analysis of
15′ 30′ 1h 2 hUT
pathways affected by BMPdentine inducer) and EMD (enamel
matrix derivatives) on dental pulp stem
cells. Differences can be seen by the
increase of expressed Wnt pathway
proteins for EMD (a) and the increase of
Smad 4 for BMP-
pathway (b). Unpublished data.
ameloblasts to pre-
2 (a known
2in the canonical BMP
pSmad2/3
Smad4
GAPDH
direction of movement of the odontoblast layer (Figure1.2). This signalling is comprised principally
of DSPP, enamelysin and ameloblastin(20). However, it is evident that the Wnt and Sonic hedgehog
(SHH) pathways and the deposition of a baseline collagen matrix are also essential for the correct
cell lining(18, 21). With this, attempts were made to use enamel derivative proteins to induce pulp
repair. However, there are differences between the differentiation induced by enamel matrix
derivatives (EMD) and mineral trioxide aggregate (MTA), for example, even if the gene expression
changes are similar (Figure1.3). Clinically, none of the materials used for pulp capping and/or
regenerative procedures is capable of synthesizing and secreting the original signalling molecules
BMP-2
15′ 30′ 1h 2 h
EMD
15′ 30′ 1h 2 hUT
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layered by ameloblasts. This does not mean that the regeneration process is impossible.
Theliterature has shown examples that the dentine itself is a major reservoir of multiple growth
factors that can activate multiple signalling pathways into DPSCs(22). More importantly, these
growth factors can be mobilized by current materials used for pulp capping (e.g. calcium hydroxide
and MTA), which can be of great importance in chemotaxis prior to inducing cell differentiation
and production of the dentine barrier(23–25).
The Role ofthe Apical Papilla
Last, but not least in tooth development, is the role of the apical papilla. While considered an
embryonic tissue, the apical papilla is a mesenchymal tissue that remains active until the complete
maturation of the tooth (Figure1.4). After the deposition of the first layers of dentine at the crown
level and subsequent formation of the primitive pulp tissue, the remnants of the dental papilla
continue to work with the Hertwig’s epithelial root sheath in order to guide the development of the
cementum, alveolar bone, radicular dentine and periodontal ligament(26, 27). As with the crown,
the signalling between epithelial and mesenchymal cells is responsible for tissue differentiation
ofthe stem cells present in this tissue and consequent dentinogenesis. Even after the tooth
eruption,
the root(s) will continue to develop and, until the development is complete, the apical papilla will
remain. As the original dental papilla, the apical papilla is rich in undifferentiated cells with multipotent capacity, which makes it a great source of stem cells for revitalization or revascularization
procedures(28).
This understanding of the tooth development process brings insight into the repair process
induced by VPTs. The first associated with the presence of undifferentiated cells and its
potential to differentiate into odontoblasts and other cell types necessary for repair and
regeneration. Second, it is expected that an effective material will closely mimic the interactions between these mesenchymal stem cells and the epithelial cells that formerly underlined
the primitive pulp tissue. Third, molecules that participate not only in the differentiation
process but also in the cell recruiting events may be of interest for using dental materials.
This can happen directly or indirectly as dentine serves as a reservoir for many of these factors, and materials can be affected by extracting them from the tissue and mobilizing them for
cell intake.
Figure1.4 Histologic image from the
apical papilla, detaching from the root apex
of an immature third molar. Observe the
high cellularity and vascularization of the
tissue, which can be preserved partially and
used for endodontic regenerative purposes
(HE, 40×).
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Stem Cell Reserve andHealing/Regeneration Potential ofthe
Dental Pulp
Current concepts on pulp regeneration rely on stem cells, either by transplantation or by attracting
stem cells present in the body to the area, also known as cell homing. The same can be said about
the repair process: it is known that the pulp has a reparative potential, and most of this potential
comes from the cellularity of the tissue. Notably, previous research has shown that older patients
present lower healing potential in the pulp, and that conservative pulp procedures should be mostly
reserved for young patients. This comes from the fact that older connective tissues will have their
cell turnover and cellularity negatively affected, and the constant production of secondary dentine
determines that cells in this ‘older’ pulp tissue may enter senescence(29, 30). The aged pulp tissue
will appear radiographically to have smaller pulp chambers and clinically have less profuse bleeding
and higher levels of fibrosis. This means that a tooth that has been previously decayed with tertiary
dentine production and then restored is pathologically ‘older’ than a completely sound tooth. It is
important to differentiate this pulp age from the patient’s age. With this, the literature has shown
that the patient’s age has little effect on the success of VPT procedures(31).
Of course, a clinical evaluation of the cellularity of the pulp tissue is not possible currently; in
fact, dentistry, despite all the evolution in the last century, still does not have a reliable way to
determine an exact pulp diagnosis (see Chapter3). Thus, the professional opting for a conservative
or radical procedure needs to take other factors into account besides the patient’s age. Indeed, the
patient’s age still plays a role as the fibre: cell ratio changes over time. But other factors such as
clinical diagnosis, dental history and presence of tertiary dentine and/or internal calcifications are
also signs that the pulp tissue in question has already been irritated and responded. Having a clinical understanding that an aged tissue can respond less ideally in a young patient and vice versa is
essential to explain both success and failure in VPT.
Pulp Vascularization andits Clinical Implications
As with most connective tissues, the dental pulp can be seen as comprised of structural fibres,
cells, nerves, blood vessels and lymphatic vessels. However, when looking closely, it is clear that
the pulp is more complex; it is made up of different anatomical zones and is encircled by a hard
tissue secreted by odontoblasts (Figure1.5). The impact of these anatomical attributes and other
factors on the potential of the pulp to heal and/or on the determination of success in clinical procedures will be discussed further below.
Among these complexities, the internal anatomy of the pulp chamber and canals is one of the
factors contributing to the evolution of inflammatory and reparative processes. As stated above, the
pulp is surrounded by dentine, which is a hard tissue. This makes it impossible for the pulp tissue to
swell and/or expand in case of inflammation. The apical foramen is the main point of entry for the
neurovascular bundles, and the more immature the tooth is, meaning that the foramen is increased
in size (open- apex), the better the tissue vascularization is. This happens even in inflammatory
events and, thus, can result in better clinical outcomes when performing pulp capping and/or
pulpotomy procedures. In addition, due to their small size and inconsistent numbers, lateral canals,
for example, do not appear to contribute significantly to the presence of neurovascular bundles.
If clinical outcome and success of VPTs is considered, the presence of vascularization is
important, as it is responsible for providing the immune cell response and the nutrients for a
successful repair. It is known that angiogenesis can be induced by the presence of hypoxia, which
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Figure1.5 Histologic image from the pulp
tissue encircled by dentine/enamel structure
(HE, 40×).
is observed in a connective tissue that achieves 200 μm in size (32). The dental papilla does not
have any blood vessels until it achieves this diameter, and cells start to suffer from the lack of
oxygen. This lack of oxygen induces the production of hypoxia- inducible transcription factor
– alpha (HIF1- alpha), which then induces the activation of vascular endothelial growth factor
1
(VEGF), responsible for cell differentiation and formation of new blood vessels(33, 34). This factor
3
is important and explains why the coronal pulp is much richer in microvessels per mm
radicular pulp, as its volume is larger. Moreover, HIF-
1alpha has been connected to increased
than the
production of tertiary dentine in inflamed pulps, suggesting these factors can also contribute to the
repair process(33, 35). It is essential to understand the role that hypoxia plays, not only in pulp
development but also in other aspects of the homeostasis of the tissue. After any sort of damage
and/or induced inflammatory process by the presence of bacterial lipopolysaccharides (LPS), it is
possible that small areas of the pulp tissue will undergo different levels of hypoxia. The lack of
oxygen in this tissue has the primary participation in the angiogenic process, particularly by the
expression of HIF1- alpha and VEGF (Figure1.6). Other molecules are also related to angiogenesis,
more specifically the B(IL-
1beta) and tumour necrosis factor- alpha (TNF- alpha)(37), which all have a clear effect on both
cell lymphoma 2 (Bcl- 2) (36) and cytokines such as interleukin 1 beta
the angiogenic and inflammatory processes. Moreover, the presence of hypoxia is known to activate
DPSC differentiation and consequent mineralization(35, 38, 39), illustrating the close connection
between the pulp damage and the repair process.
In addition to the simple presence of blood vessels, it is well- known that a vascularized tissue
can also respond more effectively to harm from bacteria and materials in order that the tissue can
be repaired or regenerated properly. Many studies on pulp regeneration have been focusing on the
importance of vascularization and have specifically shown that, without proper angiogenesis, true
regeneration cannot occur. In this context, the use of angiogenic factors such as the above-
cited
HIF1- alpha or the VEGF has been proven as a way to promote angiogenesis by the differentiation
of DPSC into endothelial cells and by assisting with anastomosis with the host original blood
vessels (2, 33). This process is essential to allow for the complete fill of the pulp space with
functional tissue and, in the case of repair, VEGF, for example, could be used as an adjuvant to
promote adequate oxygen levels for the pulp tissue during the initial inflammatory process and,
consequently, allowing the cells to migrate and differentiate.
Besides blood vessels, lymphatic vessels appear to be of major importance in regulating
inflammatory and repair processes. While the literature has opposing views on this subject, with
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LPS, bacterial products, other
chemical and physical factors
1
leading to inflammation
IL-1beta
TNF-alpha
5a
2
HIF-1alpha
3
pulp tissue under hypoxia due
to inflammation
(e.g. increase of pressure due
to inflammatory exudate)
200 μm
4
Bcl-2
VEGF
new blood vessels
5b
Figure1.6 Mechanisms of hypoxia- induced dentinogenesis and angiogenesis. (1) Induction of cell
response due to LPS, bacterial products and/or other irritants; (2) promotion of vasodilation by cytokines;
(3) increase in inflammatory exudate on the affected tissue; (4) hypoxia; (5) as the hypoxia reaches 200 μm,
affected cells release HIF- 1alpha, which directly affects odontoblasts to induce tertiary dentine and/or
induces the release of VEGF and Bcl- 2 to form new blood vessels.
data showing the complete absence of this type of structure (40, 41) and others showing its
presence(42–45), it is important to understand how lymphatic drainage can contribute to control
inflammation. In this context, lymphatic vessels have the initial function of removing catabolites
from the tissues, including inflammatory cells, cytokines and dead bacteria, amongst others,
directing them to lymph nodes, which then will work on these drained fluids to eliminate harmful
factors(46). When looking at this function in pulp tissue, the controversy regarding the presence
or absence of lymphatic vessels continues: in theory, the absence of lymphatic vessels would be a
confirmation that pulp does not recover from intense inflammatory processes, as the cytokines and
other harmful factors will be chronically acting on the tissue without proper drainage. However,
even the studies that show the lack of lymphatic capillaries in the dental pulp state that these
studies were done under normal conditions(40, 41), while other studies have specifically shown
the presence of these capillaries under inflammation(42, 45). All this conflicting information may,
in fact, indicate that the pulp indeed lacks lymphatic circulation, although lymph angiogenesis
appears to occur in the presence of pulp damage and inflammation. Additionally, the fact that the
pulp tissue is only vascularized from the apical region can also be responsible for the lack of
removal of these factors. As the pulp containment within hard tissue walls can contribute to that
as blood vessels are dilated, there is an increase in intrapulpal pressure and, consequently, if
lymphatic vessels are present, they would be less effective given this pressure. Among the studies
that show the presence of lymphatic vessels, there are some observations that are also important,
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such as the fact that these types of vessels are more prevalent close to the apical region and not in
the coronal pulp tissue(47). Clinically, this can also explain why pulpotomies tend to be successful,
as the radicular pulp tissue can be more resilient to the inflammatory process because it has higher
capability to modulate the inflammatory process due to the presence of lymphatic vessels. Again,
these facts can be only observed if pulp vitality is preserved, since true regeneration is not yet
achieved clinically, at least in any clinically available technique.
Pulp Innervation andits Contribution toPhysiologic Changes
Maintaining pulp vitality also results in the presence of functional nerves in the tissue. The pulp is
a highly innervated tissue, with many of the nerve bundles close to the odontoblast layer. The pulp
possesses sympathetic nerves, which are associated with the blood vessels and their ability to
respond with vasodilation or constriction and the ability to participate in the ‘neurogenic
inflammation’ process(48, 49). Evidently, the normal physiology (homeostasis) of the tissue is only
maintained in case the tissue is preserved properly. This is factually true for the pulp tissue;
however, the physiology of the dentine itself is completely dependent on the maintenance of the
pulp tissue, with an interrelationship so intertwined that these two tissues together have been
called the dentine- pulp complex. This relationship starts during tooth development stages and
goes on through the tooth’s life, and some of the functions discussed here are very important in
terms of the long- term prognosis of the tooth.
Much has been presented about pulp tissue physiology and how its structure affects treatment
outcomes. When discussing pulp preservation, the first factor that comes to mind is the ability of
the tooth to respond to pain, and it serves as an alert in case something is wrong. Many dentists
have had the experience that a devitalized tooth (a root canal- treated tooth) became decayed, and
the carious lesion evolved with no warning underneath a crown, resulting in extensive structure
loss and an unrestorable tooth. One can then infer that the pulp tissue, when present, can ‘detect’
this carious lesion, leading the patient to seek dental work before such destruction occurs. Indeed,
the pulp has this ability, and it all comes down to the presence of vitality in the tissue.
As stated previously, the pulp tissue is rich in nerves. The most important ones from the point of
view of tooth response are the A- delta and C fibres(50), which include both afferent and postganglionic sympathetic fibres. A- delta fibres are myelinated which are bundled in a plexus that is
mostly located between the core of the pulp tissue and the cell- free zone. These fibres lose their
myelin layer (but not their Schwann cells) when penetrating the cell- rich and cell- free zones until
reaching the odontoblast layer and, occasionally, the dentine tubules. The literature does not show
any evidence of real synapses between these fibres and odontoblasts(51, 52). Independently of the
presence or absence of these connections, the close relationship between these A- delta fibres and
the dentine is of major importance in many aspects of pulp physiology, from dentine sensitivity
(for example, the hydrodynamic theory) to inflammatory and repair responses(53, 54).
A- delta fibres conduct the stimuli very quickly, and this translates into a response that is sharp
and of short duration. So, when cold is applied on the tooth surface, the dentinal fluid present in
the tubules moves towards the pulp, and this movement stimulates the A- delta fibres present
either in the tubules or close to the odontoblast layer. In healthy tissue, this response rapidly
subsides as the body temperature stabilizes the fluid movement, eliminating the stimulus to the
nerve fibres(53). Sometimes, patients present with hypersensitivity due to exposed dentine. The
principle for the painful response is the same. However, the process known as neurogenic
inflammation has been proven to happen in the pulp tissue also(55, 56). In this case, the stimulation
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Dentin stimulation
recruitment
Increase in blood flow
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of a sensory (afferent) nerve fibre can lead to the release of substance P, which is a neuropeptide
with major role in the inflammation(55). Substance P has been detected as released from C fibre
terminals and is associated with increased pulpal blood flow and, consequently, vasodilation(57).
Other neuropeptides such as calcitonin geneimmune response, with a dose-
dependent effect on recruiting T- cells, for example (58).
related peptide (CGRP) also work towards the neural
Understanding this process may bring therapeutic options, as it is clear that the nerves and all
neuropeptides detected in the pulp tissue can impact pain control, immune response and
inflammation (59) (Figure 1.7). Stimulating the pulp nerves due to tooth damage can lead to
hyperalgesia and allodynia at the trigeminal ganglion level (60), so the sensitized tissue will
respond to pain more easily. This response, either from a normal pulp or for a pulp with reversible
pulpitis, is a good way to raise the patient’s awareness and assist the provider with a pulp diagnosis
that does not demand a more radical intervention. In the case of a carious tooth, this inflammatory
process can continue to develop. With this and the presence of bacteria, areas of necrosis and
anoxia can be observed in the pulp tissue and these fibres, due to the presence of their Schwann
cells, start to lose their efficiency as these cells depend on oxygen to survive(54). This helps to
explain why tissues with irreversible pulpitis have lingering pain when tissues are stimulated with
cold. The speed at which the stimulus is conducted is not the same anymore, and the increase in
intrapulpal pressure can lead to a more severe response. This intrapulpal pressure, on the other
hand, will not be stimulating the A-
delta fibres but, instead, will be stimulating the C fibres. These
fibres, as stated above, are unmyelinated nerve fibres, generally located in the pulp core. In this
context, these fibres do not respond to cold stimulus, for example, as they are not connected to the
Vasodilation
Figure1.7 Mechanism of neurogenic inflammation. Dentine stimulation can lead to C fibres to express
and release both substance P and CGRP. Substance P can induce an increase in blood flow and vasodilation,
while CGRP can induce the recruitment of T- cells. CGRP also induces pulp cells to express IL- 8, which can
increase the sensitization of neural fibres and make the inflammatory cycle persistent.
Inflammatory
exudate
Substance P
CGRP
IL-8
(hypersensitization)
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tubular fluid movements. In a normal pulp tissue, these fibres would not be responsible for typical
tooth pain; however, given the fact that they respond with a more dull, aching pain, they can assist
in diagnosing referred pain, for example(61). In cases of pulpitis, they tend to lead to the most
painful episodes, particularly due to their effectiveness in detecting changes in intrapulpal
pressure(57). These fibres are also more resistant to hypoxia, meaning that they can be responsive
even in cases where the pulp tissue is close to complete necrosis. Again, responses like this can
only be used for diagnosis in vital pulps and losing these references can impair the awareness
about harmful processes like caries.
Pulp Response toRestorative Processes
Preserving tooth vitality also has an impact on restorative processes. In vitro studies have shown that
the presence of pulp tissue alone does not change dentine hydration and, consequently, does not
make the tooth more brittle(62). On the other hand, there is evidence showing that the absence of
dentinal fluid and consequent maintenance of the collagen structure of the dentine may affect the
bonding process(63, 64). The hybridization process with adhesive and the etched dentine can be
more effective if a certain level of moisture is present, particularly if the moisture comes from the
dentinal tubules. The correlation between the use of dental materials and dentine permeability can
also serve as a good reason for keeping pulp vitality, as it is wellchemical, bacterial and thermal stimuli on the dentine surface can have an impact on how the pulp
tissue responds(65). When applying dental material against dentine, even without pulpal exposure,
one can expect a tissue reaction. Initially, the tissue reaction comes from the simple fact that dentine
is being cut by a bur with heat(66). When that happens, some odontoblast extensions will be cut or
overheated, leading those cells to their death and consequent release of cytokines that will initiate
the inflammatory process. Most of the time, in healthy pulp tissue, this will not result in more
damage as the stimulus is of short duration. As we are going to discuss later in this chapter, the
inflammatory process is, in fact, necessary for adequate repair and even for regenerative procedures.
With respect to dental material application, studies have shown, for example, that eugenol can
have a soothing effect on the pulp, even though it is very cytotoxic(67, 68), indicating that dosage
and composition are significant when attempting pulp repair. In addition, when looking for repair,
a vital pulp provides an environment where the factors released by the dentine due to the action of
dental materials can be effective in promoting cell differentiation, control of inflammation,
angiogenesis and other actions(23, 24). In this context, as obvious as it can be, preserving the pulp
vitality is essential to promote adequate repair and dentinogenesis, all necessary for adequate
healing of the tissue and reestablishment of the homeostasis of the dentine/pulp complex. The
same can be said about the presence of bacteria: the vital pulp tissue, besides reporting tissue
destruction with pain, can also be responsible for the initial line of defence against microorganisms.
There is a lot of information on how bacteria affect odontoblasts and how, even in cases where the
pulp is not exposed, bacterial byproducts are known to have an effect on the pulp tissue and, as
explained for dental materials, this reaction can start an inflammatory reaction and consequently,
the production of tertiary dentine in an attempt to recover tissue homeostasis. Recent studies show
that even small amounts of LPS and lipotheicoic acid (LTA) can induce alkaline phosphatase, an
indicator of mineralization, in DPSCs (69, 70). This information, associated with dentine
permeability, shows the role played by the pulp tissue in the protection of the tooth when faced
with microbial and chemical agents. The molecular aspects of this protective effect will be discussed
in the next subsection.
known that the application of
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Pulp Vitality andInflammation
Much has been researched and discussed about the effects of inflammation on pulp repair.
Currently, it is well established that the reparative process needs some level of inflammation to be
effective. While we still cannot control the ‘threshold’ level of inflammation clinically, the knowledge of the participating molecules in both processes is essential to improve the odds of being able
to do so in the future.
The molecules involved in the inflammatory process are numerous and have different specific
functions. Among these, it is possible to name proinflammatory cytokines, for example. These
include some of the already discussed molecules (e.g. HIF(IL-
1beta), interleukin 6 (IL- 6), interleukin 8 (IL- 8) and others. Most of them have been shown to
be associated to pulp tissues with irreversible pulpitis, a fact that can also be reproduced with
pulp cell cultures under stress(71–76). These studies have proven a direct correlation between
levels of cytokines and inflammatory status. However, we have also shown that even a healthy
pulp has basal levels of those cytokines, and, as we have demonstrated in previous work, they can
be localized in the odontoblast layer of a nonproinflammatory cytokines may also be involved in the regular dentinogenesis process and that
this process may be exacerbated in case of higher levels of these cytokines, leading them to induce
more tertiary dentine and, consequently, collaborate in the tissue repair(71, 74, 77–80). These
papers show that this process can occur on a number of different fronts, such as the activation of
the Wnt pathway by the inflammatory cytokines, the activation of substance P by neural stimulus
and even the direct release of cytokines by competent cells (e.g. odontoblasts, DPSCs and
fibroblasts) when challenged by bacteria and their subproducts (Figure1.8). As stated above, the
repair process is dependent on some level of inflammation, and the expression of these cytokines
opens opportunities in the translational research field. The first one can be associated with the
qualification and quantification of these cytokines to facilitate pulpal diagnosis and increase
treatment success rates(81). Although this is still not feasible clinically, the understanding of the
development of pulpal inflammation, its stages, and the cytokines involved with success and
repair is essential to keep pulp vitality. On another note, there are opportunities for using
immunotherapy as a way to control and modulate these cytokines and, thus, direct the repair
process(82).
inflamed tissue (74). This supports that
1alpha) but also interleukin 1 beta
Mechanisms ofPulp Repair
Other molecules involved in the pulp repair are transcription factors associated with cell
differentiation and mineralization, which is essential to protect the pulp tissue from the external
environment. Transcription factors are proteins that encode a number of genes and thus regulate
a large number of functions in cell metabolism and response. The literature is rich in examples of
transcription factors that participate in the dentinogenesis process, namely Runx2(21, 35, 69, 83)
and homeobox genes (Msx1, Msx2, Dlx3, Dlx5, Sox2), which can be expressed to direct the cell
differentiation and consequently the proper tissue formation(83–87). It is important to emphasize
that the pulp capping materials may have a role in this expression and that the sequence where
these proteins are expressed also plays a role in determining the outcome towards an osteodentine
or tubular dentine phenotype(16). Recently, some focus has been put on the role of microRNA in
the inflammatory process. MicroRNA (miR) are small molecules, more specifically single- stranded
RNA molecules, that regulate the expression of genes. They can be present in the blood and inside
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E
D
A
PMN and other
immune cells
Figure1.8 Molecular responses to activate pulp inflammation. The presence of bacteria in different levels of
dentine and their products can activate odontoblasts, which will subsequently release cytokines such as
IL- 1beta and IL- 8 (A). These same products can lead to the activation of nerve fibres and the release of
substance P and CGRP (B). The complement and immune systems can also be activated by dead cells (C) and
immunocompetent pulp cells (D), by the presence of necrosis (e.g. leading to release of HIF- 1alpha) and also
cytokines released from pulp cells (Il- 6, IL- 8 and others). When bacteria reach the pulp, they will face
macrophages and activate the immune system themselves (E). The activation of the immune system is essential
for pulp repair, as it will induce cell differentiation and activation of the existent and viable odontoblasts.
C
and immune cells
B
cells and are seen as an alternative for controlling diseases. This makes them candidates for
epigenetic regulation in pulp repair as well. In the last few years, there has been a large amount of
research being directed at identifying the miRNA in the inflamed pulp tissue. MicroRNAs were
observed as playing a role in inflammation, opening the prospect that regulating them can assist as
well in the control of tissue inflammation(88–90). Furthermore, another aspect of microRNA is
that these molecules are not only responsible for the control of inflammation, but they also play a
role in cell differentiation and tissue repair, with some of these molecules having action on both
processes(89, 91). More specifically, pulp studies have identified many different microRNAs, and,
unfortunately, this makes it difficult to discuss specifically which ones would be ideal targets. For
example, there is data on miR- 126 controlling the expression of IL- 1beta in human pulps(88); that
miR- 21 can regulate many cytokines and factors in LPS- induced dental pulp cells (90); miRlet7c- 5p is responsible for blocking inflammatory pathways and promoting osteogenic
differentiation(91).
Thus, when looking at VPT and the maintenance of the pulp tissue, we focused more on the
aspects that can lead to a successful pulp- induced regeneration. In a still unpublished study, our
group identified the miR- 200c as one of the targets based on the collection of healthy and inflamed
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