Perit Dial Int
29(Supplement_2):
21-27
2009
© 2009 International Society for Peritoneal Dialysis
Part 2: Cellular and Molecular Biology of the Peritoneum
and Peritoneal Dialysis |
INTRINSIC CELLS: MESOTHELIAL CELLS — CENTRAL PLAYERS IN REGULATING INFLAMMATION AND RESOLUTION
Susan Yung and
Tak Mao Chan
Department of Medicine, University of Hong Kong, Hong Kong SAR, PR
China
Correspondence to: S. Yung, Department of Medicine, University of Hong Kong,
Queen Mary Hospital, Pok Fu Lam Road, Hong Kong SAR, PR China.
ssyyung{at}hkucc.hku.hk
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ABSTRACT
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Background: Preservation of the structural and
functional integrity of the peritoneum is essential to maintain the dialytic
efficacy of the peritoneal membrane. Although much improvement has been made
to peritoneal dialysis (PD) fluids, they remain bioincompatible, and together
with peritonitis, they continue to induce peritoneal inflammation and
fibrosis.
Method: This article reviews the putative factors that
mediate mesothelial cell inflammation during PD, and the mechanisms by which
mesothelial cells attempt to regulate and resolve peritoneal
inflammation.
Results: The mesothelium is the first line of defense
to foreign particles and chemicals in the peritoneal cavity. Constant exposure
of the mesothelium to the bioincompatible constituents of PD solutions results
in denudation of the mesothelium and loss of the peritoneal cavity's
protective layer. Detached mesothelial cells in PD solutions have the capacity
to replenish the mesothelial layer through their ability to migrate and attach
to areas of denudation. Mesothelial cells synthesize a plethora of growth
factors, matrix proteins, and proteoglycans that aid in the reparative process
and regulate the formation of chemotactic gradients that are essential for
infiltration of leukocytes to sites of injury.
Conclusions: Far from being bystanders in peritoneal
function, mesothelial cells have been shown to play a dynamic role in
peritoneal homeostasis and immunoregulation. Studies have highlighted the
potential use of mesothelial cells in gene therapy and cell transplantation,
both of which may provide novel therapeutic strategies for the preservation of
the peritoneum during PD.
KEY WORDS: Mesothelial cells; inflammation; cytokines; epithelial-to-mesenchymal transdifferentiation; hyaluronan; proteoglycans.
Although peritoneal dialysis (PD) is now considered an established form of
renal replacement therapy, its long-term success depends on the structural
integrity of the peritoneum, an organ that nature did not evolve for the
purpose of PD. Compelling evidence from in vitro and in vivo
studies have highlighted the harmful nature of bioincompatible PD solutions on
the structural, functional, and morphologic properties of human peritoneal
mesothelial cells (HPMCs), attributed in part to chronic intraperitoneal
inflammation
(1–3).
The present review provides an overview of peritoneal inflammation consequent
to chronic PD and of the putative role of HPMCs in the regulation and
resolution of peritoneal inflammation.
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THE MESOTHELIUM
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The mesothelium consists of a monolayer of specialized epithelial cells
that line the surfaces of the peritoneal, pleural, and pericardial cavities
(4,5).
Regardless of their anatomic origin or species, mesothelial cells constitute a
homogenous population that predominantly exhibits an elongated, flattened, and
squamous morphology (4). At
sites of tissue injury, mesothelial cells with a cuboidal phenotype have also
been identified, and these cells have been shown to be in a highly reactive
state, indicated by an abundance of intracellular organelles (mitochondria,
rough endoplasmic reticulum, Golgi bodies, and vesicles). The apical surface
of HPMCs is endowed with numerous microvilli that serve to increase the
surface area of the cells for the absorption of solutes. Microvilli can trap
water and serous exudates, and also prevent friction injury to the HPMCs
(4).
Contrary to previous belief, mesothelial cells are not passive cells; they
are now recognized as metabolically active cells that can dynamically
participate in peritoneal homeostasis. Functional properties attributed to
HPMCs include the control of fluid and solute transport, immune surveillance,
and regulation of inflammatory processes and wound healing
(Table 1).
Through their ability to synthesize numerous cytokines, growth factors,
matrix proteins, and intracellular adhesion molecules, and their ability to
present antigens to lymphocytes, HPMCs play a critical role as
immunomodulators during peritoneal injury and inflammation
(4,6–9).
The introduction of PD more than three decades ago has provoked much
interest in the biology of mesothelial cells. In the peritoneal cavity, HPMCs
represent the largest population of resident cells, whose primary function is
to provide a non-adhesive and protective layer against the invasion of foreign
particles and injury to the peritoneum consequent to chemical or surgical
insult.
The HPMCs isolated from omental specimens possess morphologic and
biochemical properties identical to the properties identified in peritoneal
mesothelial stem cells. Cultured HPMCs therefore provide a most suitable tool
for the study of the multifaceted properties of mesothelial cells, and
determine how the structural and functional properties of these cells are
modulated under the influence of PD
(5,10,11).
However, in designing experimental protocols for in vitro studies
that pertain to mesothelial inflammation, it is essential to take note of the
age of the tissue donor, because studies have demonstrated that HPMCs isolated
from older donors are associated with an inflammatory and senescent phenotype
even in the absence of an exogenous stimulus
(12).
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MEDIATORS THAT INDUCE PERITONEAL INFLAMMATION
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Inflammation is defined as the body's immediate reaction to injury, a
tightly regulated and protective response that endeavors to remove the
underlying insult and to initiate a healing process
(13). Acute inflammation is a
short-term process that results in healing and restoration of the normal
architecture and function of the tissue, but by contrast, chronic inflammation
is a prolonged and uncontrolled response characterized by concomitant active
inflammation, tissue damage, and attempts to resolve inflammation. The
constant exposure of tissue to the insult would inevitably result in
neoangiogenesis, tissue fibrosis, and thus destruction of the tissue.
Instillation of bioincompatible PD solutions, formation of glucose degradation
products and advanced glycation end-products, peritonitis, and uremia
(Table 2) all contribute to
peritoneal inflammation
(1,3,14,15),
which is characterized by increased vascular permeability, activation and
expansion of the peritoneal macrophage population, recruitment of infiltrating
cells to sites of injury, release of pro- and anti-inflammatory mediators, and
increased matrix protein synthesis and tissue remodeling.
Bacterial peritonitis is a major complication of PD and a leading cause of
technique failure. Lipopolysaccharide (LPS) derived from both gram-positive
and gram-negative organisms is a potent mediator of peritoneal inflammation
that induces the production of chemokines and proinflammatory cytokines
(16). Mesothelial cells have
been shown to secrete interleukin 8 (IL-8), monocyte chemoattractant protein 1
(MCP-1), and macrophage inflammatory protein 2 upon exposure to bacterial
products or stimulation with IL-1β or tumor necrosis factor 
(TNF)
(17,18).
Recognition of bacterial pathogens by the peritoneum is mediated in part by
toll-like receptors (TLRs) that can detect microbial
components—ubiquitous to most microbes—that induce inflammation by
activation of nuclear factor 
B (NF-B) and signaling transduction
pathways, and induction of chemokines
(16,19).
Human peritoneal mesothelial cells have been shown to constitutively express
TLR-1, -2, -3, -4, -5, and -6, and TLR-4 expression is increased in murine
peritoneal mesothelial cells after LPS stimulation
(19). Whether similar
expression can be observed in HPMCs remains to be elucidated.
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THE ROLE OF PROTEOGLYCANS AND GLYCOSAMINOGLYCANS IN THE REGULATION OF PERITONEAL INFLAMMATION
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A critical component of any inflammatory response is the rapid recruitment
of leukocytes from the bloodstream to the site of the injury. This event in
the peritoneum is regulated by HPMCs through the creation of a chemotactic
gradient across the mesothelium. Chemotaxis is a multistep process that
requires chemokine presentation, interaction with chemokine receptors, and
activation and induction of intracellular signal transduction
(20). In addition to their
interaction with their high-affinity receptors, the seven transmembrane G
protein–coupled receptors, chemokines have also been shown to bind
glycosaminoglycans (GAGs) located on the cell surface and basement membranes
(20). Studies have
demonstrated that GAGs can significantly contribute to the control of
chemokine functions. In this respect, GAG–chemokine interactions can
prevent chemokines from undergoing proteolysis and can induce chemokine
oligomerization, a process that establishes a more activated form of the
chemokines as compared with their monomeric counterparts
(21,22).
Although peritoneal macrophages and mast cells release chemokines into the
peritoneal environment, HPMCs in culture have also been shown to synthesize
numerous chemokines that include MCP-1, RANTES, and IL-8 in response to
cytokine stimulation (23).
Also, HPMCs have been shown to secrete a number of proteoglycans that include
decorin, biglycan, and perlecan
(24–27).
The GAG content of these proteoglycans all have the potential to regulate
chemokine activity and create a chemotactic gradient. It is therefore possible
that these macromolecules play a pivotal role in regulating inflammation in
the peritoneum.
The GAG hyaluronan (HA), which consists of the repeating disaccharide units
N-acetyl-D-glucosamine and D-glucuronic acid, has a
ubiquitous tissue distribution
(28), and HPMCs have been
shown to synthesize large amounts of HA
(29–31).
Hyaluronan is a major component of the mesothelial glycocalyx, where it
contributes to the protective, nonadhesive nature of the mesothelial cell
surface. In a healthy individual, HA is synthesized as a macromolecule with a
molecular weight in excess of 106 Da. Hyaluronan participates in
the structural architecture of the peritoneum and can regulate inflammation
through its ability to sequester free radicals. Through its ability to
interact with water molecules, HA can generate a hydrated micro-environment,
especially in the pericellular matrix that allow cells to migrate and divide
(28). Synthesis of HA is
increased during inflammation, conveying to the resident cells a signal to
initiate tissue survival and repair. Increased HA synthesis promotes the
generation of intercellular cables that act as an inflammatory matrix that
binds and retains leukocytes in their inactive form at sites of injury
(32). Hyaluronan cables can
also serve as scaffolds that prevent the loss of matrix proteins within the
extracellular milieu during inflammation and can induce resident and
infiltrating cells to secrete growth factors to aid in the reparative
process.
High molecular weight HA can assist in the regulation and resolution of
inflammation, but HA fragments possess proinflammatory properties that can
activate the inflammatory cascade. Tissue injury is associated with an
increased turnover of HA, and failure to remove its degradation products
results in unrelenting inflammation. Low molecular weight HA possesses
functional properties that are distinct from those of the parent molecule.
These properties include the induction of chemokines and cytokine secretion,
angiogenesis, cell proliferation, and suppression of apoptosis. Haslinger and
co-workers demonstrated that HA fragments induced IL-8 and MCP-1 in HPMCs
through the activation of NF-B and signal transduction pathways
(33). Increased levels of HA
found in the spent dialysate of patients maintained on PD are indicative of
chronic inflammation, and HA levels are further increased in patients with
peritonitis
(29,31).
Szeto et al. suggested that increased HA levels in PD fluids can
predict patient survival
(34).
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ALTERED MESOTHELIAL PHENOTYPE DURING PERITONEAL INFLAMMATION
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Under physiologic conditions, HPMCs adopt a polygonal cobblestone
epithelial morphology. However, under the influence of inflammation and
peritonitis, HPMCs can undergo epithelial-to-mesenchymal transdifferentiation
(EMT), a complex and reversible process that endows the cells with a
migratory, invasive fibroblastic phenotype
(2). The transition from
mesothelial to mesenchymal cell phenotype is accompanied by disruption of
intercellular junctions, loss of cell polarity and reorganization of the
cytoskeleton, with the aim of initiating the reparative processes and
restoration of peritoneal homeostasis. We have demonstrated that EMT in HPMCs
is associated with polymerization of the actin cytoskeleton and increased
levels of both high and low molecular weight HA
(30,35),
the latter suggestive of a dual role for HA in tissue injury and wound
healing. Factors that can initiate EMT in HPMCs include transforming growth
factor β1 (TGFβ1), IL-1β, epidermal growth factor and
hepatocyte growth factor, all of which are increased during peritoneal
inflammation and peritonitis. Prolonged exposure of HPMCs to these peptides
results in delayed regression back to the epithelial phenotype and
exacerbation of the fibrotic pathway.
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CHANGES TO THE PERITONEUM CONSEQUENT TO PERITONEAL INFLAMMATION
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Peritoneal dialysis occurs between the apical aspect of the mesothelial
cell monolayer and the inner surface of peritoneal capillary endothelial
cells. Therefore, any structural or morphologic changes to the mesothelium
would have a significant effect on PD
(36,37).
Peritoneal biopsies obtained from PD patients have shown a reactive
mesothelium, in which cells have become enlarged, weakly adhesive, and
apparently degenerated (36).
Denudation of the mesothelial monolayer is observed in numerous established PD
patients, a finding that is associated with vasculopathy and submesothelial
thickening (37). The loss of
the protective mesothelial monolayer allows the bioincompatible PD solutions
to infuse into the submesothelium to continue its detrimental effect on the
peritoneal membrane.
Can the mesothelium be repopulated to preserve the functional integrity of
the peritoneum during PD? Numerous theories have been put forward to explain
how a denuded mesothelium can be restored, including centripetal migration of
HPMCs; exfoliation from adjacent surfaces of proliferating HPMCs, which then
settle on the denuded area and replicate; and the existence of free-floating
pluripotent serosal cells that settle on the injured mesothelium and
differentiate into new mesothelial cells, which then repopulate the
mesothelial monolayer
(4,38).
During PD, exfoliation of HPMCs into the peritoneal cavity is a common
phenomenon. The ability to culture HPMCs from spent dialysate suggests that
these detached cells are viable. However, the phenotype of these cells is
varied and can consist of cells with an epithelial morphology; large,
senescent cells containing multiple nuclei and multiple vacuoles; and cells
with an elongated, fibroblastic appearance
(2). It is therefore possible
that these cells may contribute to restoration of the mesothelium after
insult, in a process that involves detachment of mesothelial cells from
adjacent areas free of damage and subsequent migration to areas of injury
where the cells reattach and proliferate to remesothelialize the injured
monolayer. However, removal of these cells from the peritoneal cavity during
PD exchanges and alterations in phenotype and function may compromise complete
remesothelialization. Of interest and significant importance is the
observation that normally adherent HPMCs remain viable after detachment from
the mesothelium (39).
Understanding the mechanisms through which detached HPMCs can prevail over the
apoptotic pathway and maintain their proliferative property will provide
further insight into the mechanisms by which HPMCs can relieve and resolve
peritoneal inflammation.
The role of the coagulation cascade in the generation of fibrin following
tissue injury is well understood. A fine balance exists between peritoneal
synthesis and catabolism of fibrin in the normal peritoneum. If fibrinolytic
activity is compromised because of chronic inflammation, fibrin accumulation
may result in formation of peritoneal adhesion
(40). During peritoneal
inflammation, increased levels of TNF, IL-1β, TGFβ1, and LPS
can regulate the activities of pro- and antifibrinolytic mediators. Plasmin is
critical for the reparative processes in the peritoneum because it can
regulate inflammation and cell migration and degrade fibrin and matrix
proteins. Under inflammatory processes, the fibrinolytic activity of plasmin
is compromised by the increased synthesis of plasminogen activator inhibitor
1, with the result that peritoneal healing is impaired
(40).
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STRATEGIES TO REDUCE PERITONEAL INFLAMMATION
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Compelling evidence now points to the critical role of HPMCs in maintaining
the integrity and functional properties of the peritoneum. Mesothelial cell
transplantation has been heralded a novel therapeutic strategy that has the
potential to reduce peritoneal inflammation and structural changes to the
peritoneum, and thus restore tissue functions
(39). However, knowledge of
the mechanisms that regulate mesothelial repair and cell activation remains
limited.
Hekking et al. demonstrated that apparently successful mesothelial
cell transplantation in Wistar rats after the induction of experimental
peritonitis was accompanied by mesothelial cell activation and the subsequent
induction of MCP-1 and HA
(41). Are these results an
indication that transplantation of cells obtained from an unrelated animal or
individual may result in the peritoneum treating the cells as
"foreign" particles that, despite their ability to be transplanted
successfully, induce the one thing that the technique was used to relieve? It
is therefore essential—before even contemplating clinical
studies—to address the problem of cell activation and onset of
inflammation.
Other researchers have suggested that it would be possible to cultivate
HPMCs from omental specimens that have been obtained from pre-dialysis
patients and to store them in liquid nitrogen until required for
reimplantation (42). Although
this concept is most fascinating, would such a technique be truly realistic
given the lifespan limitation of HPMCs and their survival under liquid
nitrogen without compromise to their morphologic and functional properties?
Given the peritoneum is already impaired as a result of PD, could it be
assumed that all cells administered would be transplanted? If not, what is the
consequence of the excess cells? Are they cleared by inflammatory cells, or do
they remain in the peritoneum where they undergo cell necrosis or apoptosis
and induce inflammation, an event that they were specifically introduced to
fight against?
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CONCLUSIONS
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There is now compelling evidence to underscore the essential role of HPMCs
in peritoneal homeostasis and in the regulation of peritoneal inflammation.
The ability to culture HPMCs has provided researchers with an excellent tool
to investigate changes in cell morphology, biochemical profiles, and the
functions of these multifaceted cells. However, it is notable that, depending
on the micro-environment, these cells have the capacity to switch from an
epithelial phenotype that contributes to the resolution of peritoneal injury
and inflammation to an invasive, migratory, and activated mesenchymal
phenotype that contributes to neoangiogenesis, fibrosis, and peritoneal
dysfunction. Further studies into the molecular aspects of these cells will
allow the mechanisms that transform constitutive peritoneal mesothelial cells
to a proinflammatory and fibrotic phenotype to be deciphered, leading to
suitability for mesothelial transplantation.
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ACKNOWLEDGMENTS
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Part of this work was supported by a Committee on Research and Conference
Grant (10207295) and the Wai Hung Charity Foundation. Dr. Susan Yung is
supported by the Endowment Fund established for the Yu Professorship in
Nephrology awarded to Dr. Tak Mao Chan.
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TOP
ABSTRACT
THE MESOTHELIUM
