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Review Article

The Significance of Epithelial Rests of Malassez


in the Periodontal Ligament
David Keinan, DMD, MSc, MHA, PhD, and Robert E. Cohen, DDS, MS, PhD
Abstract
Introduction: The purpose of this review was to
describe the function of epithelial rests of Malassez
(ERMs) in a variety of physiologic and pathologic conditions. Methods: The authors performed a PubMed
search on the term epithelial rests alone or in combination with Malassez. Relevant articles were categorized into primary subtopics and related to current and
historic literature. Results: The review was divided
into 7 subtopics. Those sections discuss possible roles
for ERM in a variety of physiologic and pathologic
processes. Conclusions: ERMs have a fundamental
role in root development, protect against root resorption, and are involved in reparative and regenerative
functions of the pulp and periodontal tissues including
apexogenesis and periodontal healing. They also appear
to be involved in pathologic processes such as the development of oral cysts and tumors. (J Endod 2013;39:582
587)

Key Words
Epithelial rests, periodontal ligament, root development

From the Department of Periodontics and Endodontics,


University at Buffalo, State University of New York, Buffalo,
New York.
Address requests for reprints to Dr David Keinan, Department of Endodontics and Periodontics, School of Dental Medicine, University at Buffalo, The State University of New York,
Squire Hall, Buffalo, NY 14214-30932. E-mail address:
davidkei@buffalo.edu
0099-2399/$ - see front matter
Copyright 2013 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2013.01.004

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mbryonic dental development involves ectomesenchymal interaction to participate


in tooth formation (1). The cells of the external and internal epithelium proliferate
from the cervical loop of the dental organ to form a double layer of cells known as the
Hertwig epithelial root sheath (HERS) (2, 3). Once the root sheath forms, it rapidly
initiates root formation, extending from the cervical loop to the apical foramen and
eventually fragmenting, which is mediated by apoptosis (46), to form a fenestrated
network around the tooth (2). In the longitudinal section, this fenestrated network
appears as a discrete cluster of epithelial cells known as the epithelial cell rests of Malassez (ERMs) (2, 7). These cell clusters undergo cellular turnover and can gradually
increase in size with increasing age (8).
It is well established that during embryonic development there is an increased
expression of various genes and proteins by ERMs and the HERS (917). The
differentiation of HERS cells in culture has been observed after 14 days, with
stratified assembly of ERMs and overexpression of osteopontin and deposition of
calcium salts, suggesting a role in the secretion of hypocalcified material during the
early stages of cementogenesis (18). It was also shown that there is a direct interaction
between ERMs and fibroblasts, leading to increased production of proteins such as type
IV collagen and laminin by both cell types (19, 20). Transmission electron microscopic
studies using extracted teeth from a healthy periodontium and from different age groups
showed the assembly of the ERMs and neural endings in the periodontal ligament (PDL)
(21). There appears to be an intimate relationship between pinocytotic vesicles in the
enclosing cells of Ruffini-like receptors and vesicles in the neural ending at the level of
ERMs, suggesting a functional involvement of the ERM during nerve fiber development
(21). A decrease in the number of ERMs with increased age also was observed (21, 22).
The ERMs formed in late-stage root development in mice were found along the acellular
cementum and have been hypothesized to differentiate from the inner epithelial root
sheath cells (23).
A multipurpose culture chamber has been used to enable the proliferation and
emigration of ERMs in a manner similar to that observed during wound healing
(24). ERM proliferation was associated with outer basal-like cells, free ribosomes,
and the formation of actin-containing microfilaments as well as a loss of gap junctions
and inner tonofilament-rich prickle-like cells (24). The high nucleus:cytoplasm ratio,
the presence of tonofilaments, and relatively abundant mitochondria also have been
shown as ultrastructural features of ERM clusters (2527). Electron microscopy of
rat molars showed that after 30 days from birth, epithelial cells form oval-shaped
epithelial islands, with collagen fibrils remaining in the intercellular spaces (25). These
studies also showed hemidesmosomes and tight junctions connecting between the
epithelial cells, with a layer of basal lamina that separates those cells from the connective
tissue (25, 26). However, in more mature rats, there was an increased number of
epithelial cells, with collagen fibrils only rarely observed in the cytoplasm and the
intercellular spaces, and an almost complete lining of basal lamina (25). These results
suggest that the ability of epithelial cells to phagocytize collagen fibrils is a crucial step in
their maturation. It also was found that the epithelial rests of 9-week-old rats had more
cells and almost complete lining of basal lamina than 5-week-old rats, suggesting that
the basal lamina is involved in the formation of the ERMs (28). As the root sheath fragments, ectomesenchymal cells of the dental follicle penetrate between the epithelial
fenestrations and become apposed against the newly formed root dentin, finally differentiating into cementoblasts (2). ERMs were also found to affect acellular cementum
formation, especially in the early stages of root formation (29). It has been hypothesized

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Review Article
that ERMs function to maintain a fixed PDL space through participation
in a noncalcification mechanism during tooth eruption (30).
In the following sections, we present the role of ERMs in different
clinical situations, including pulp calcification, ankylosis, tooth movement, and root-end closure, as well as in pathologic situations such
as the development of cysts and tumors. Understanding their function
may assist in the development of potential therapeutic strategies.

Methods
The authors performed a PubMed literature search on the term
epithelial rests on January 16, 2013, which yielded 1003 results.
The results were further screened to include articles from 1970 and
later that were in English and related to the subject of the review based
on the abstract. The results were further categorized into primary
subtopics as presented herein. An attempt was made to focus on
more clinically oriented articles as well as those judged to be more relevant to practicing endodontists. A total of 132 references remained and
were included in this review.

Results
We have categorized our findings into 7 subtopics: pulp calcification, apical root closure, periodontium, orthodontic tooth movement,
enamel pearls, pathologic lesions, and hyperplastic pulpitis. These
subtopics emphasize the possible role that ERMs may play in both
the physiologic and pathologic process.

ERMs and Pulp Calcication


The etiology of pulp calcification and diffuse or separated denticles
is unknown. Proposed etiologic factors include genetic predisposition
(31); orthodontic tooth movement; circulatory disturbances in pulp;
age (32); long-standing irritants such as caries, extensive restorations,
and chronic inflammation (33); and idiopathic factors (34). Unfortunately, these factors do not provide clear insight into the pathogenesis or
mechanism of pulp calcification.
One proposed explanation is based on the interactions between
the epithelium inside the pulp canal and the surrounding pulp connective tissue (35, 36). Two weeks after perforation into the pulp chambers
of rat molars, histologic analysis revealed migration of HERS-forming
islands of epithelial cells, with large nuclei and cytoplasm partially surrounded by subsequently formed osteodentin and cementum (37).
Similarly, it was shown that pulp stones also may form around epithelial
cells by inducing adjacent mesenchymal cells to differentiate into odontoblasts (38).
Calcifying nanoparticles, which are self-propagating macromolecular complexes with bacteria, have been proposed as serving as a nidus
for dental pulpal calcifications (39). The calcifications are initiated on
aggregations of carbonate apatite on the surface of those nanoparticles
that also display cytotoxic effects on murine and human fibroblast cell
lines and eventually might lead to degeneration of the pulp (39). Inagaki
et al (40) showed that diabetic rats with increased pulpal calcifications
overexpress osteopontin and alkaline phosphatase. The intense histologic staining of osteopontin around the calcified particles also suggests
a potential role of osteopontin in pulp calcification (40).
ERMs and Apical Root Closure
The irregular and variable structure of the apical region of human
teeth represents special challenges during endodontic therapy (41),
particularly in cases with incomplete root formation. Because root
development of a permanent tooth is completed up to 3 years after eruption, any irreversible damage to the dental pulp of an immature permanent tooth will result in a short and wide-open root apex. Studies also
JOE Volume 39, Number 5, May 2013

have shown that cells might proliferate and migrate from an adjacent
undamaged PDL into the affected area (42, 43). It has been shown
that the ERM cells are distributed in the PDL in a network-shaped
manner along the root surface and in the furcation region, primarily
in teeth with incomplete root formation (30).
Frank (44) proposed several normal healing responses to apexification (ie, an induced apical barrier), which result in different locations of the barrier in relation to the main canal. The regenerative
capability of ERMs was shown in rabbits as cord- or net-like formations
or as isolated islands near the cementum (45). Trowbridge and Shibata
(46) also showed that epithelial cell rests can retain the ability to
undergo cell division. A mechanism for apical barrier reformation after
the use of calcium hydroxide is apposition of osteoid (bone-like or
cementum-like) or osteodentin (4749). Torabinejad et al (50)
showed a complete layer of cementum when using mineral trioxide
aggregate as a root-end filling material in monkeys. However, there
are few histologic studies reporting the involvement of ERMs in the
formation of the calcified barrier (5154). Therefore, it is plausible
that ERMs might be involved in cases of apexification in which
cementum is laid down but absent when bone-like tissue ingrowth is
observed.
Apexogenesis is the process by which root development continues
because of the preservation of pulp vitality. Ghafoor (55) highlighted the
role of HERS and dental papilla in the continued root formation of
immature permanent teeth. Recently, revascularization procedures
have been proposed for the treatment of immature permanent teeth
with necrotic pulp to promote thickening of canal walls and continued
root development (5662).
Shimizu et al (63) described the histologic findings of tissue
formed in the canal space of an immature permanent incisor after revascularization and showed the ability of the HERS to survive despite irreversible pulpitis but without apical periodontitis. More than one half of
the canal was filled with loose connective tissue having layers of
epithelial-like cells (similar to the HERS) surrounding the root apex
(63). It also was suggested that detachment or separation of the
HERS from the main root might be able to induce continued yet separated root development (64, 65). However, because the HERS is very
sensitive to trauma and, once destroyed, there is cessation in normal
root development (66), the role of additional cellular processes also
should be considered.

ERMs and the Periodontium


Periodontal Healing. ERMs are involved in dental root development and regeneration of the attachment apparatus (6770). During
root morphogenesis and cementum repair, ERM cells may undergo
an epithelial-to-mesenchymal transition and differentiate into cementoblasts (67, 71). The junctional epithelium of the erupted permanent
tooth may have arisen from the cell rests, remnants of the dental
lamina, or gingival epithelium depending on the presence or absence
of inflammation (72). ERMs have been hypothesized to participate in
apical migration of the junctional epithelium during marginal periodontitis (73) and to have a critical role in remodeling of the socket after
autotransplantation (74). The early expression of apin, which is
a protein expressed during enamel organ development that is produced
by maturation-stage ameloblasts and junctional epithelium, after the
disruption of periodontal integrity suggested that this protein might
be part of the cascade of events leading to the activation of ERMs during
periodontal healing and regeneration (75). After the induction of periodontal disease, ERMs were more evident in the PDL along the root
surface and in the root furcations (75).
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ERMs might influence cementum regeneration by activating the
secretion of matrix proteins that are usually expressed during normal
tooth development (76, 77) and also might play a role in regulating
the homeostasis and width of the PDL and in PDL regeneration (78).
Hamsters that were treated with heparan sulfate mimetic after the induction of periodontitis exhibited an increase in the number of ERMs,
which were previously depleted by periodontitis (79). This was followed by a greater expression of bone morphogenic protein-3 by
ERMs (79). Bone morphogenic protein-3 stimulates the proliferation
of mesenchymal stem cells and inhibits bone formation and, therefore,
might prevent bone overgrowth and tooth ankylosis (80, 81). However,
in a study investigating PDL homeostasis, it was concluded that ERMs are
unlikely to play an important role and might not be a prerequisite for its
repair and maintenance (82). Similarly, ERMs were not found to reform
after regenerative surgical procedures (83).
Ankylosis and Root Resorption. ERMs are embedded in the
tissues of the PDL near the root cementum (84). The functions of these
cells in the maintenance of the PDL have been investigated in a monkey
incisor model (85). Explants of enamel organ or oral squamous epithelium were placed in experimental root surface cavities of extracted and
subsequently replanted monkey incisors. After 8 weeks, histologic evaluation of the experimental cavities showed a reparative cementum layer
on the dentinal surface, with islands of epithelium in the periodontal
connective tissue and no bone found within the periodontal space
(85). Control cavities and cavities originally containing squamous
epithelium also showed regeneration with reparative cementum, but
the alveolar bone had grown into the cavities (85). These findings
were suggestive of a physiologic role for odontogenic epithelium and,
in particular, ERMs, for maintaining the width of the PDL and preventing
dentoalveolar ankylosis (85). Similar findings showed that ERMs participate in periodontal repair during experimental root resorption in rats
and were immunoreactive for osteopontin and ameloblastin (76).
Histologic evaluation of intentionally replanted dog mandibular
incisors showed that areas of resorption were absent on root surfaces
in which ERM were present (86). Similarly, extracted human primary
teeth revealed surfaces with and without resorption depending on the
presence of epithelium (87). In those areas with resorption or with
signs of resorption repair, the epithelial rests of Malassez appeared
as small, scattered islands with adjacent innervation (87). It also was
shown that denervation led to dentoalveolar ankylosis with a decrease
in the width of the PDL. Upon regeneration of the Malassez epithelium
10 weeks after denervation, the width of the PDL significantly increased
(88). These findings suggested that the Malassez epithelium might be
involved in the maintenance of PDL, is able to negatively regulate root
resorption, and is associated with acellular cementum formation (88).

ERMs and Orthodontic Tooth Movement


ERMs are closely correlated with maintaining a stable width of the
PDL and are always located closer to the cementum than to the alveolar
bone (89). It has been shown that ERMs synthesize and secrete latent
collagenase (90), and that they proliferate and increase in size in
conjunction with experimental tooth movement (91, 92). ERMs were
observed in resorption areas on root surfaces of extracted premolars
after rapid palatal expansion using transmission electron microscopy
with 3-dimensional reconstruction (93). The existence of ERMs in
the resorption areas and in correlation to the resorption level suggests
their possible involvement in root resorption (93). Another study
showed increased levels of epidermal growth factor in ERMs during
orthodontic movement at both the tension and compression sides, suggesting their role in bone remodeling (92). Mechanical stretching (by
an orthodontic screw on epithelial cells derived from ERMs) showed
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a significant increase in the number of epithelial cells synthesizing


DNA after 30 minutes of stretching (94). Immunocompetent PDL cells
also have been found in the vicinity of ERMs in both normal PDLs and
during experimental orthodontic tooth movement, suggesting
a morphologic and functional role of ERM in such movement (95,
96). It was proposed that the role of ERMs in preserving
cementogenesis during mechanical stress may be mediated by
expression of vascular endothelial growth factor, heat shock protein
70, and specifically osteopontin (97).
The adhesion of osteoclasts to mineralized tissues specifically by
the avb3 integrin plays an important role in the process of bone resorption during orthodontic treatment (98). The overexpression of ERM
avb3 integrin and b3 integrin subunits by osteoclasts during experimental tooth movement provides further evidence that ERMs might
be involved in bone resorption, remodeling, and tooth movement
(98). Ultrastructural features of the ERMs indicate that they also might
be involved in mediating repair after tooth movement by increasing
cementogenesis (99). It has been suggested that ERM-mediated orthodontic root resorption can be regarded as an exaggerated response to
the loss of PDL homeostatic control (100).

ERMs and Enamel Pearls


Enamel pearls are small rounded nodules that most frequently
develop in the furcation area of molars and consist either of enamel
alone or enamel containing a small core of tubular dentin. Positive
staining for amelogenin has been observed in the enamel-like tissues,
indicating the presence of well-developed ameloblasts (101). Similarly,
Hamamoto et al (37) suggested that ERMs could differentiate into
ameloblast-like cells. Subcultured ERMs combined with primary dental
pulp cells seeded onto scaffolds showed enamel-like tissues at 8 weeks
after transplantation. Positive staining for amelogenin was observed in
the enamel-like tissues, indicating the presence of well-developed
ameloblasts in the explants. The capability of the enamel epithelium
of the HERS to not only differentiate into ameloblasts but also to produce
amelogenin also has been shown (37). The capability of those enamelproducing ameloblast-like cells might suggest their involvement in the
mechanism of enamel pearl formation.
ERMs and Pathologic Lesions
ERMs can proliferate, under experimental or pathological
conditions, resulting in the formation of odontogenic cysts and tumors
(102106). The squamous odontogenic tumor is a rare, benign, locally
infiltrative neoplasm of the jaws that appears to originate from ERMs
(107110). The proliferative effect on epithelial cells stimulated by
interleukin (IL)-1 may play a role in evoking an inflammatory
response and stimulating ERMs to proliferate to form a radicular cyst
(111). It was suggested that dental cysts arise from the proliferation
of ERMs in a focus of inflammation stimulated by pulpal necrosis of
the associated tooth (112).
The proliferation of ERMs has been proposed as an essential step
in the pathogenesis of radicular cyst development (111, 113122). The
precise mechanism involving epithelial proliferation and cyst formation
is still unclear (123). Studies showed an increased expression of
a variety of molecules such as the epidermal growth factor (118) and
heat shock protein 27 (115) by ERMs as well as IL-1 a, IL-6, IL-8,
and granulocyte macrophage colonystimulating factor (116). Gao
et al (120) suggested that this proliferation might be associated with
a significant change, from an unusual epithelial phenotype to that of
a stratified noncornifying epithelium in which some simple epithelial
keratins are coexpressed. Correspondingly, ERMs showed immunoreactivity with different monoclonal antibody probes to the epidermal
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Review Article
growth factor receptor with a staining pattern showing a gradual
decrease toward the periphery of the clusters (124). The amount of
epidermal growth factor receptor expression by ERM within periapical
granulomas was lower than in epithelial rests not related to inflammation within adjacent connective tissue (124). It also was proposed that
this proliferative process of ERMs is mediated by low concentrations of
IL-1 (111).
ERMs associated with local inflammation were thought to participate in the pathogenesis of 325 cases of inflammatory paradental cysts
(125). In another study, the existence of oxytalan fibers in a biopsy
obtained from a lesion supported the origin of a tumor from ERMs in
the periodontal membrane of the related tooth although it displayed
typical histologic features of the desmoplastic variant of ameloblastoma
(126). An additional study (127) reported 2 separate developmental
odontogenic cysts associated with an unerupted mandibular third
molar. Radiologic and histologic examinations resulted in a diagnosis
of a lateral periodontal cyst and a follicular (dentigerous) cyst. The
authors concluded that this unusual occurrence provided evidence
that the periodontal cyst might originate from ERMs (127). In a mouse
study, ERMs were stimulated to proliferate, stratify, and form a differentiated squamous epithelium (128). The involvement of ERMs in keratocyst formation was also hypothesized because of disturbances in
hedgehog signaling in both humans and mice (128). It was suggested
that interactions between odontoblasts and ERMS with Smad4 gene
deletion might lead to the formation of a keratocyst (129). In contrast
to those studies, the odontogenic keratocyst may alternatively arise from
the proliferation of the residue of the dental lamina, possibly as a hamartomatous abnormality, and not from ERMs (112).

ERMs and Hyperplastic Pulpitis


Hyperplastic pulpitis, also known as pulp polyp, is an uncommon
chronic inflammatory process predominantly occurring in primary and
immature permanent molars. The associated teeth have an abundant
blood supply through the wide apices. A pulp with a rich blood supply
has a better ability to resist bacterial infection and subsequent inflammation than an older pulp (130). Clinically, such teeth show extensive
coronal destruction characterized by protrusion of the pulp tissue
(131). The asymptomatic and chronic nature of that process is caused
by the wide drainage from the inflamed tissue and the outgrowth of the
pulp tissue that prevents increased intrapulpal pressure (132).
However, masticatory forces may produce irritation and bleeding.
The management of the lesion is by endodontic treatment or through
extraction if unrestorable. The histologic appearance of the lesion is
characterized as chronic inflammation enveloped by stratified squamous epithelium. The source of the epithelium is thought to be desquamated epithelial cells from the oral mucosa (131). However, ERM also
could be considered as a possible etiologic factor in the pathogenesis of
hyperplastic pulpitis.

Summary
Proposed roles of ERMs in the oral cavity have been described in
the context of embryonic development as well as in physiologic and
pathologic processes. Understanding their role may help to develop
new therapeutic strategies. This is especially relevant in the era of
increased development of regenerative procedures.

Acknowledgments
The author denies any conflicts of interest related to this study.

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