Respirology (2002) 7, 171191

REVIEW ARTICLE

Mesothelial cells: Their structure, function and role in

serosal repair
S E. MUTSAERS
Asthma and Allergy Research Institute and Department of Medicine, University of Western Australia,
Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

Mesothelial cells: Their structure, function and role in serosal repair

MUTSAERS SE. Respirology 2002; 7: 171191
The mesothelium is composed of an extensive monolayer of specialized cells (mesothelial cells) that
line the bodys serous cavities and internal organs. Traditionally, this layer was thought to be a simple
tissue with the sole function of providing a slippery, non-adhesive and protective surface to facilitate intracoelomic movement. However, with the gradual accumulation of information about serosal
tissues over the years, the mesothelium is now recognized as a dynamic cellular membrane with
many important functions. These include transport and movement of fluid and particulate matter
across the serosal cavities, leucocyte migration in response to inflammatory mediators, synthesis of
pro-inflammatory cytokines, growth factors and extracellular matrix proteins to aid in serosal repair,
release of factors to promote both the deposition and clearance of fibrin, and antigen presentation.
Furthermore, the secretion of molecules, such as glycosaminoglycans and lubricants, not only
protects tissues from abrasion, but also from infection and possibly tumour dissemination.
Mesothelium is also unlike other epithelial-like surfaces because healing appears diffusely across
the denuded surface, whereas in true epithelia, healing occurs solely at the wound edges as sheets
of cells. Although controversial, recent studies have begun to shed light on the mechanisms involved
in mesothelial regeneration. In the present review, the current understanding of the structure and
function of the mesothelium and the biology of mesothelial cells is discussed, together with recent
insights into the mechanisms regulating its repair.
Key words: biological phenomena, cellular structures, mesothelium, pleura, wound healing.

INTRODUCTION
The mesothelium was first described by Bichat in
1827.1 Using histological techniques, he observed that
the serous cavities were lined by a single layer of flattened cells similar to those of the lymphatics. In 1880,
Minot,2 in a detailed study of the embryological
origins of the mesothelium, initially referred to this
layer as the epithelial lining of mammalian mesodermic cavities and subsequently proposed the term
mesothelium.3 Embryologically, the mesothelium
develops from the mesodermal tissue between 8 and
18 days of gestation, depending on the species.46 In

Correspondence: Steven Mutsaers, Asthma and

Allergy Research Institute, Ground Floor E Block, Sir
Charles Gairdner Hospital, Verdun Street, Nedlands, WA
6009, Australia. Email: mutsaers@cyllene.uwa.edu.au

humans, this occurs around day 14, with cells gradually differentiating from round or cuboidal cells to
elongated flattened cells that line the coelomic
cavities.4,6
Despite the early discovery and description of the
mesothelium, it has only been in recent years that
its importance, both in health and disease, has been
realized. It is not just a limiting protective layer that
stops the organs from sticking together, but a dynamic
structure regulating serosal responses to injury, infection and disease. The present review focuses on the
recent advances in our understanding of the structure
and function of mesothelial cells and the mesothelium
and the mechanisms regulating its repair.

STRUCTURE OF MESOTHELIAL CELLS

AND THE MESOTHELIUM
The mesothelium extends as a monolayer over the
entire surface of the three serosal cavities (pleural,

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SE Mutsaers

pericardial and peritoneal) and, in the male, it also

lines the sac that surrounds the testes. Mesothelium
that covers the internal organs is referred to as the
visceral mesothelium, whereas the parietal mesothelium lines the body wall. Morphological studies of
the mesothelium of several mammalian species, including rat, mouse, dog, hamster, rabbit, horse and
humans,1,723 have demonstrated, with minor exceptions, that mammalian mesothelium is essentially
similar, irrespective of species or anatomical site. In
addition, histochemical studies have supported these
structural findings.24,25

HISTOLOGY
The mesothelium forms a monolayer of predominantly elongated, flattened, squamous-like mesothelial cells, approximately 25 mm in diameter, with
the cytoplasm raised over a central round or oval
nucleus.26 The cells rest on a thin basement membrane supported by connective tissue stroma, which
varies in quantity and quality between the three
serous cavities, between visceral and parietal serosa
and between species.20,22,27 Surface specialization, in
the form of characteristic microvilli and occasional
cilia, is also seen (Fig. 1).
Although the mesothelium is composed predominantly of squamous-like cells, cuboidal mesothelial
cells can be found in various areas, including the
septal folds of the mediastinal pleura, the parenchymal organs (liver, spleen), the milky spots of the
omentum and the peritoneal side of the diaphragm
overlying the lymphatic lacunae.13,18,19,28 Cells that are
morphologically similar to these cuboidal mesothelial cells can also be identified after injury or stimulation of the serosal surfaces2931 (Fig. 2).

Figure 2 Scanning electron micrograph of fan-shaped and

plump elongated activated mesothelial cells (large arrows)
with aggregates of small spherical inflammatory cells (small
arrows) attached to their surface at the edge of a serosal
lesion 24 h after injury. Bar, 21 mm. Reproduced with permission from Mutsaers et al.31

ULTRASTRUCTURE
Ultrastructural analysis of squamous-like and
cuboidal mesothelial cells show differences between
their nuclei and cell organelles. Squamous-like
mesothelial cells have a round or ovoid nucleus,
whereas the nuclei of cuboidal cells are larger and
contain a prominent nucleolus.8,17,18,32 Organelles of
the squamous-like cells are located centrally, close
to the nucleus. These cells contain microtubules and
microfilaments, glycogen, few mitochondria, a poorly
developed Golgi apparatus and little rough endoplastic reticulum (RER).9,17,18,32 The microfilaments are
located parallel to the cell surface and are situated
deep in the cytoplasm.9 Cuboidal mesothelial cells
have abundant mitochondria and RER, a welldeveloped Golgi apparatus, microtubules and a comparatively greater number of microfilaments,9,18,32
suggesting a more metabolically active state.

MICROVILLI

Figure 1 Transmission electron micrograph showing

normal testicular mesothelial cells with a thin attenuated
cytoplasm (large arrow) and surface microvilli (medium
arrow) resting on a basement membrane (small arrow).
Elongated fibroblast-like cells (F) are located beneath the
basement membrane within the tunica albuginea, surrounded by collagen (arrow heads) and other connective
tissue. Bar, 1.4 mm.

The luminal surface of the mesothelial cell has a welldeveloped microvillous border, with microvilli
varying in length, shape and density (Fig. 3). Variations in the concentration of microvilli have been
reported on mesothelial cells of different organs,
between adjacent cells and on the surface of individual cells.11,18,19,28 The entire microvilli population is
also labile, with the number of microvilli expressed
on each cell changing under different physiological
conditions.15 Differences in the number of microvilli
on regenerating mesothelial cells have also been
reported and it has been suggested that their
concentration reflects functional adaptation.15,18,33,34
These changes are also associated with an alteration
in surface charge.34 This may reflect changes in the
composition of the negatively charged glycocalyx
that covers the mesothelial cell surface35 or may be
due to trapping by microvilli of proteins and other
molecules from the serosal fluid, protecting the

173

Mesothelial cell: Structure and function

have begun to elucidate the molecular mechanisms

regulating junction formation. A number of protein
components associated with these junctional complexes has been identified in a variety of cell types.4144
Mesothelium expresses E-, N- and P-cadherins,
although, unlike the epithelium, N-cadherin predominates.45 Furthermore, membrane-associated
expression of zonula occludens (ZO)-1 has been
demonstrated in intact sheets of normal mesothelium.46 Expression of other junctional proteins, such
as catenins and occludin, has not been studied.

STOMATA

Figure 3 Scanning electron micrograph of normal visceral

mesothelium showing a carpet of microvilli on the surface
of the cells. Cell borders are not easily discernible. Bar,
3.23 mm.

mesothelium from surface friction and ensuring its

integrity.9,11,14,18,34,36

VESICUL AR SYSTEM
Mesothelial cells also have a well-developed system
of vesicles and vacuoles; most are micropinocytic,
but multivesicular bodies and large vacuoles can be
found.37 Like the microvilli, the concentration of these
structures varies between cells and sites. Generally,
the visceral mesothelium has more vesicles than the
parietal mesothelium and the vesicles are more
numerous along the luminal cell surface, often in
contact with the plasmalemma.8,9,22,32,36,38 These vesicles are involved in transport of fluids and particulates across the mesothelium, because experimental
studies have shown tracer particles up to 100 nm can
traverse the cell by pinocytic transport.8,36,39

Von Recklinghausen, in 1863,47 described the presence of stomata, cavities at the junction of two or
more mesothelial cells, which he postulated allowed
movement of fluid and particulate matter to and from
the serous cavities. Scanning and transmission electron microscopy studies combined with tracer studies
have clearly demonstrated their existence, although
there is still much debate about their location, density
and function.1214,19,28,39,4856 Stomatal openings, 3
12 mm in diameter, are generally found in those
regions, where cuboidal mesothelial cells are present,
such as on the peritoneal side of the diaphragm or
over the omental milky spots. These openings provide
a direct access to the underlying submesothelial
lymphatic system, allowing rapid removal of fluid,
cells, bacteria and particles from the serosal cavities.52,54,5658 It has also been proposed that stomata
provide a direct link between the pleural and peritoneal cavities.54,59 This may explain how inhaled
materials, such as asbestos, can enter the peritoneal
cavity and cause asbestos-induced fibrosis or malignant mesothelioma.

FUNCTION OF THE MESOTHELIUM

Classically, the two main functions attributed to the
mesothelium are to provide a protective barrier and a
frictionless interface for the free movement of apposing organs and tissues. In recent years, it has been
discovered that this tissue also plays important roles
in fluid and cell transport, initiation and resolution
of inflammation, tissue repair, lysis of fibrin deposits preventing adhesion formation and protection
against invading microorganisms and, possibly,
tumour dissemination.

CELL JUNCTIONS
MESOTHELIAL TRANSPORT
The boundaries between mesothelial cells are tortuous, with adjacent cells often overlapping. They have
well-developed cellcell junctional complexes,
including tight junctions, adherens junctions, gap
junctions and desmosomes.10,37,40 Tight junctions are
crucial for the development of cell surface polarity
and the establishment and maintenance of a semipermeable diffusion barrier. Adherens junctions are
thought to form the structural and adhesive support
of the cell layer and gap junctions are aqueous intercellular channels. Extensive studies in recent years

The mesothelium is involved in the transport and

movement of fluid and particulate matter across the
serosal cavities. Odor, in 1954,7 proposed that the
mesothelial cell surface is important in transport
across the serosal wall because the many microvilli
increase the surface area of the luminal aspect of the
cell, thereby facilitating absorption. The glycocalyx
covering microvilli also contains glycosaminoglycans,
which bind fluids, aiding adsorption.18 Studies involving various tracers have shown that particulates

174

SE Mutsaers

and solutes can be actively transported across the

mesothelium by pinocytic vesicles.8,36,39 If required,
for example when there is an elevation in extracellular fluid pressures, mesothelial cells can increase
the number of plasmalemmal vesicles.60 Using similar
tracers, transmesothelial transport has also been
shown to occur through intracellular junctions and
stomata25,36,38,6163 rather than occurring by passive
diffusion. However, others have found no evidence
to support this hypothesis.38,64,65
Studies of the enzymes associated with flattened
resting mesothelial cells and cuboidal activated
mesothelial cells have demonstrated a difference
in the enzymatic profile of each mesothelial cell
type.62,6672 The studies indicated that resting mesothelium is mainly concerned with membrane transport,
whereas cuboidal mesothelial cells have a wider spectrum of functional activities. These observations also
support the concept that flat resting mesothelial cells
can become metabolically active cuboidal cells.

SECRETION OF GLYCOSAMINOGLYCANS
AND SURFACTANT
The mesothelial cell secretes surface glycosaminoglycans, predominantly hyaluronan, which have been
demonstrated ultrastructurally both on the surface
and within pinocytic vesicles of mesothelial cells.73
From this observation, it was unclear whether the
glycosaminoglycans are produced by or merely
transported through the mesothelium. However,
several observations support the hypothesis that
mesothelial cells produce glycosaminoglycans
in vivo. Hyaluronan is not derived from the circulation but is locally produced.74 An increase in the
concentration of hyaluronan is associated with the

presence of activated cuboidal mesothelial cells in

pleural effusions.75,76 Mesothelial cells in culture
synthesize hyaluronan7781 which is upregulated following injury,81,82 and is assembled into hyaluronancontaining pericellular matrix coats.83 The function
of the hyaluronan-containing coat is not known, but
it has been proposed that it may protect the cells from
viral infections and the cytotoxic effects of lymphocytes and may be important in differentiation.83
Furthermore, it may also play a role in protecting
serosal membranes from adhesion formation84,85
and tumour cell dissemination and growth.86,87
Dobbie and Lloyd88 reported that following tannicglutaraldehyde fixation, lamella bodies, similar to
those described in type II pneumocytes, could be
visualized at the ultrastructural level within and
on the surface of mesothelial cells. In vitro, rat
and human mesothelial cells are capable of synthesizing large amounts of phosphatidylcholine, the
major constituent of lamella bodies and pulmonary surfactant.89,90 These findings provide evidence
to suggest that mesothelial cells also produce and
secrete a lubricant surfactant similar to type II
pneumocytes.91

INFL AMMATION
Mesothelial cells are metabolically active cells that
participate in serosal inflammation by secreting
various pro-, anti- and immunomodulatory mediators. These include prostaglandins and prostacyclin,
chemokines, nitric oxide (NO) and reactive nitrogen
and oxygen species, anti-oxidant enzymes, cytokines
and growth factors, extracellular matrix (ECM)
molecules and products of the coagulation cascade
(Table 1). These mediators are released in response
to bacterial endotoxins and cytokines,92 asbestos,93 or

Table 1 Molecules produced by mesothelial cells

Molecule
Cytokines
IL-1
IL-6
IL-15
CSF (G, M, GM)
Chemokines
IL-8
MCP-1
RANTES
GRO-a
IP-10
SDF-1
Eotaxin
Growth factors
TGF-b
PDGF
FGF
HB-EGF
VEGF
ET-1

Site

Species

Stimulus

References

Pl, Per
Pl, Pet
Pet
Pl, Pet

H
H
H
H

EGF, TNF-a, LPS

TNF-a, IL-1
IFN-g
IL-1, TNF-a, EGF, LPS

111, 115
113, 115117
114
111, 115

Pl, Pet

H, R

Pl, Pet
Pet
Pet
Pet
Pl, Pet
Pl

H, R
H
H
H
M
H

IL-1, TNF-a, LPS, macrophage

CM, asbestos, talc
IL-1, TNF-a, IFN-g, LPS
IL-1, TNF-a, IFN-g
IL-1, TNF-a, IFN-g
IL-1, TNF-a, IFN-g

94, 95, 97, 99101, 103,

104, 112
98, 99, 101, 103, 104, 112
98, 99
98
98
105-107
108

Pl, Pet
Pl, Pet
Pl, Pet
Pet
Pl, Pet
Pl

H, M, R
H, M
H, M, R
H
H, M
R

IL-4, TNF-a
IL-1, hypoxia
IL-1, TGF-b
IL-1, TNF-a
IL-1, TNF-a, TGF-b

147151
152154
150, 156, 159
156, 157
156, 158
160

175

Mesothelial cell: Structure and function

Table 1 Continued
Molecule
HGF
KGF
PAF
ECM-related molecules
Collagen I
Collagen III
Collagen IV
Elastin
Fibronectin
Laminin
Hyaluronan
Surfactant
Biglycan
Decorin
MMP
TIMP
Integrins (a16, b1, b3, a4b3)
Coagulation cascade proteins
Tissue factor
tPA

Site

Species

Stimulus

References

Pl
Pl
Pl

H, R
R
R

Pl, Pet
Pl, Pet
Pl
Pl
Pl, Pet
Pl
Pl, Pec, Pet
Pet
Pet
Pet
Pl, Pet
Pl, Pet
Pl, Pet

H, R
H, R
R
R
H, R
R
H, Rb
H, M, Rb, Mk
H
H
H
H
H, Rt

Pl
Pl, Pet

H
H

Pet
Pl, Pet

H
H

TGF-b
IL-1, TNF-a, TGF-b,
thrombin, LPS

Pet
Pet
Pl
Pl

H
H
H
H

IL-1, TNF-a, IFN-g

IL-1, TNF-a, IFN-g, LPS

112, 137139, 141, 142, 193

112, 137, 142
264
263, 264

Pl, Pet

H, R

126132

Pet
Pl, Pet

H
H, R

NO radical

Pl

Reactive species
scavengers

Pl

H, R

IL-1, TNF-a, thrombin,

macrophage CM
IL-1, TNF-a
Combinations of IL-1,
TNF-a, IFN-g, LPS
Combinations of IL-1,
TNF-a, IFN-g, LPS
Asbestos

uPA
PAI
Adhesion molecules
ICAM
VCAM
E-Cadherin
N-Cadherin
Other molecules
Cyclo-oxygenase/
prostaglandins
HSP
NO

161, 162
161
160
IL-1, TNF-a, EGF, PDGF
TGF-b, EGF, PDGF, hypoxia

IL-1
IL-1, EGF, PDGF

TGF-b, PMA
TGF-b, PMA
EGF

TNF-a

170, 173, 175, 177179

170, 174, 175, 177, 178, 180
170
170, 171
170, 172, 176, 179
170
7983
8890
181
181
182184
182184
187189
222223
221, 226, 228, 230, 233,
235, 236
227, 236, 265
221, 225228, 230, 233237

119
120, 121, 123
123
124, 125

Pl, pleura; Per, pericardium; Pet, peritoneum; H, human; M, mouse; R, rat; Rb, rabbit; Mk, monkey; CM, conditioned
medium; IL, interleukin; EGF, epidermal growth factor; HB-EGF, VEGF, heparin-binding and vascular EGF, respectively; TNFa, tumour necrosis factor-a; LPS, lipopolysaccharide; IFN-g, interferon-g; G-, M-, GM-CSF, granulocyte, macrophage and
granulocytemacrophage colony stimulating factor, respectively; MCP-1, monocyte chemoattractant protein-1; GRO-a,
growth-related oncogene-a; IP-10, IFN-g-inducible protein-10; SDF-1, stromal cell-derived factor-1; PDGF, platelet-derived
growth factor; FGF, fibroblast growth factor; ET-1, endothelin-1; HGF, KGF, hepatocyte and keratinocyte growth factor, respectively; PAF, platelet-activating factor; PMA, phorbol myristate acetate; MMP, matrix metalloproteinases; TIMP, tissue-specific
inhibitors of metalloproteinases; PAI, plasminogen activator inhibitors; tPA, uPA, tissue and urokinase plasminogen activators, respectively; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; HSP, heat shock protein;
NO, nitric oxide.

instilled agents94 with the purpose of restoring normal

serosal architecture and function.
It is likely that serosal inflammation is activated
on the surface of the mesothelial cell, although this
has not been proven. For example, bacteria have been
shown to attach to and be phagocytosed by mesothelial cells,95,96 which can result in mesothelial cell
activation and release of interleukin (IL)-8.95 Interleukin-8 release is also associated with engulfment of

asbestos fibres by cells.94 Furthermore, hyaluronan

and mediators released from activated macrophages,
such as IL-1b, tumour necrosis factor (TNF)-a and
interferon (IFN)-g, are also potent inducers of neutrophil and monocyte chemokines, including IL-8,
growth-related oncogene-a (GRO-a), IFN-g-inducible
protein 10 (IP-10), monocyte chemoattractant
protein-1 (MCP-1) and RANTES by mesothelial
cells.94,97101 Mesothelial cells also release GRO-a in

176
response to IL-17, a cytokine secreted by T cells.102
Combining IL-17 with TNF-a further potentiated
GRO-a release and increased the stability of GRO-a
mRNA.102 Particulates, such as talc and asbestos, have
been shown to stimulate mesothelial cells to secrete
IL-8 and MCP-1.103,104 Levels of these chemokines can
be further increased if the cells are exposed to particulates in the presence of IL-1b or TNF-a.103,104
Neutralizing studies with MCP-1- and IL-1-specific
antibodies demonstrated significant decreases in
bioactivity for MCP-1 and IL-8, indicating that
mesothelial cell-derived MCP-1 and IL-8 play a
significant role in the chemotactic activity seen in
stimulated mesothelial cell supernatants.94
Recent studies have shown that mesothelial cells
also secrete stromal cell-derived factor-1 (SDF1)105107 and eotaxin.108 Stromal cell-derived factor-1
stimulates the growth of B lymphocyte precursors
(B1a) in vitro and SDF-1 production by mesothelial
cells may account for the selective accumulation of
B1 lymphocytes in body cavities.107 Mesothelial cells
also produce eotaxin in response to TNF-a and IL-4,
a T helper (Th)-2 cytokine. Eotaxin is a chemokine for
eosinophils and may explain why eosinophilic pleural
effusions occur in many diseases.109,110
Studies have also demonstrated that human
mesothelial cells constitutively express mRNA
transcripts for macrophage colony stimulating
factor (M-CSF) and can secrete IL-6 and M-CSF.111117
Interleukin-6 levels are also elevated in response
to IL-1b and TNF-a.113,116,117 Interleukin-6 is often
induced together with the pro-inflammatory
cytokines IL-1 and TNF-a and circulating IL-6 plays
an important role in the induction of acute-phase
reactions. Endogenous IL-6 plays a crucial antiinflammatory role in both local and systemic acute
inflammatory responses by controlling the levels of
pro-inflammatory, but not anti-inflammatory,
cytokines.118 Interleukin-1b and TNF-a also stimulate
mesothelial cells to secrete heat shock proteins
(HSP)-72/73, which may have a cell-protective function lessening mesothelial cell damage during inflammation.119 In addition, mRNA transcripts for other
cytokines, such as granulocyte stimulating factor,
granulocytemacrophage colony stimulating factor
and IL-1, can be induced by bacterial lipopolysaccharide (LPS), TNF-a and epidermal growth factor
(EGF).111,115
Mesothelial cells also produce NO and reactive
nitrogen (NO radical) and oxygen (O2 radical, H2O2
and OH radical) species in vitro in response
to cytokines, bacterial products and asbestos.120123
To counteract the effect of these reactive species,
mesothelial cells contain significant quantities of
anti-oxidants. When subjected to mild oxidant stress,
the cells are protected mainly by the glutathione
redox cycle, whereas during severe oxidant exposure they require catalase-mediated protection.124
Asbestos fibres have been shown to upregulate the
expression of anti-oxidant genes (manganese containing superoxide dismutase and haem oxygenase)
in human pleural mesothelial cells;125 however, it
is likely that the endogenous anti-oxidant synthesis

SE Mutsaers

may be insufficient to counteract the injurious effects

of asbestos.
Resolution of inflammation and repair of the
serosa without fibrosis requires a downregulation
of the inflammatory response, including inhibition
of fibroblast proliferation and collagen production.
Mesothelial cells are likely to contribute to controlling
inflammation both in normal and inflamed tissue
because they have cyclo-oxygenase (COX) activity,126
expressing COX-1 and COX-2 mRNA,127,128 and metabolize arachidonic acid to release prostaglandins and
prostacyclin.127,129132 Exposure of mesothelial cells to
macrophage-conditioned medium or the cytokines
IL-1b and TNF-a resulted in an increase in the levels
of both COX-1 and COX-2 mRNA, with the greatest
increase being seen for COX-2.127

LEUCOCY TE MIGRATION
The onset of pleural, pericardial and peritoneal infections is characterized by a massive influx of leucocytes from the vascular compartment into the serosal
space.133,134 As outlined by Topley et al.,135 in order for
leucocytes to be attracted to the site of inflammation
four basic events have to occur: (i) there needs to be
a site of activation; (ii) resident cells need to be activated and signals generated to initiate the response;
(iii) there must be a chemotactic gradient to direct
leucocytes to the site of inflammation; and (iv) adhesion molecule expression must be upregulated to
allow leucocyte margination and transmigration into
the serosal space.
As discussed previously, it is likely that serosal
inflammation is activated on the surface of the
mesothelial cell with subsequent release of chemokines. Secretion of chemokines is polarized towards
the cell apical surface, creating a chemotactic gradient from the basolateral to the apical side of the
mesothelial cell.99,100,136 Using transmigration studies,
neutrophils and monocytes have been shown to
follow this gradient and traverse mesothelial cell
monolayers. Blocking this gradient with antibodies
abolished transmigration.99 These findings suggest
that, by secreting chemokines in a polarized manner,
mesothelial cells promote directed transmesothelial
migration of both neutrophils and monocytes.
Movement of leucocytes from the circulation to the
site of inflammation is facilitated by the expression of
integrins and adhesion molecules. Mesothelial cells
express several cell-adhesion molecules, including
intercellular adhesion molecule (ICAM-1), vascular
cellular adhesion molecule (VCAM-1), E-cadherin,
N-cadherin, CD49a, CD49b and CD29,40,112,137140
which can be induced by IL-1b, TNF-a and IFN-g
in vitro.138,139,141 Leucocytes express the b2 integrin
family members, lymphocyte function-associated
antigen-1 (LFA-1; CD11a/CD18) and Mac-1
(CD11b/CD18) on their surface, which are counterreceptors for ICAM-1. Interaction between LFA1/Mac-1 and ICAM-1 leads to cellcell adherence and
results in transmigration of leucocytes across
mesothelial cell monolayers. However, neutrophils

Mesothelial cell: Structure and function

showed minimal adherence to and migration across

unactivated mesothelial cell monolayers, despite an
extensive amount of ICAM-1 on the mesothelial
membrane.139 Pretreatment of the monolayers with
IL-1b induced enhanced neutrophil adherence and
migration across the mesothelial monolayer, together
with a further increase in ICAM-1 expression on the
mesothelial membrane.139 Therefore, neutrophil
migration not only required ICAM-1 expression, but
also activation and release of cytokines from the
mesothelial cells. Interleukin-8 appeared to be the
major cytokine involved, with platelet-activating
factor (PAF) and transforming growth factor (TGF)-b
playing lesser roles. The importance of ICAM-1
and LFA-1 in leucocyte transmigration across the
mesothelium was clearly demonstrated both in
pleural and peritoneal cells because the incubation of
cells with the soluble form of ICAM-1 and neutralizing antibodies to ICAM-1 and LFA-1 significantly
reduced neutrophil transmigration.100,112,138
Recently, it was shown that ICAM-1 and VCAM-1
were only expressed on the microvilli of mesothelial
cells, with VCAM-1 less numerous and on less
microvilli (24%) than ICAM-1 (90%).142 Anti-VLA-4 (a
counter-receptor for VCAM-1) does not inhibit leucocyte binding to mesothelium, whereas both antiLFA-1 and anti VLA-4 do.112 It is interesting that
adhesion molecules are only expressed on microvilli,
suggesting that leucocytes may not crawl on the cell
surface, but to and from microvilli.
It has been proposed that the main function of
microvilli is to trap proteins from the serosal fluid
to help ensure mesothelial cell integrity. However,
it seems more likely that, by modulating microvilli
density together with adhesion molecule expression,
mesothelial cells can regulate trafficking of leucocytes
into and out of the serosal cavities. This is supported
by the observation that the greatest concentration
of microvilli on mouse testicular mesothelial cells
occurred at mesothelial cell junctions 6 days after
injury, when regeneration of the mesothelium was
almost complete and inflammatory cells were being
cleared.34
A great deal is known about leucocyte influx into
an inflamed site, but the subsequent events are less
clear. It is likely that leucocyte clearance from serosal
cavities is via stomata and the draining lymphatics,143
in contrast with influx directly across the mesothelium from the vasculature. Furthermore, kinetic
studies on macrophages within the peritoneum
suggest that resident and inflammatory macrophages
are cleared at different rates.143,144 The role of the
mesothelial cell in regulating clearance of leucocytes during resolution of inflammation is yet to be
elucidated.

TISSUE REPAIR
Several studies have demonstrated that mesothelial
cells have the capacity to secrete a variety of growth
factors and ECM molecules that are likely to be
involved in inflammation and tissue repair, analo-

177
gous to that of epithelial cells. Growth factors initiate
cell proliferation and migration at the edge of a lesion
and repair cells migrate over ECM molecules that are
exposed or deposited at the wound site to cover the
injury.145,146 Growth factors, including TGF-b, plateletderived growth factors (PDGF), fibroblast growth
factors (FGF) and members of the EGF family (EGF,
heparin-binding EGF (HB-EGF) and vascular-EGF
(VEGF)) are likely to regulate this process.145,146
Cultured peritoneal and pleural mesothelial cells
have been shown to synthesize and secrete TGF-b1
and TGF-b2, with TGF-b1 levels 60-fold higher than
those of TGF-b2.147,148 Cultured mesothelial cells also
express TGF-b1 and TGF-b2 mRNA147,149,150 and TGFb1 expression has been shown by in situ hybridization
in the visceral pleura of mice exposed to intratracheal
instillation of bleomycin.151 Treatment of cells with IL1 significantly increases protein and mRNA expression of both TGF-b isoforms147,148 and the steady state
levels of the mRNA.147 Hypoxia also increases TGF-b1
and TGF-b2 mRNA levels, which is enhanced for TGFb2 in the presence of exogenous TGF-b1.149 From this
finding, it was proposed that changes in the TGFb1/TGF-b2 ratio may reduce scarring and fibrosis
in serosal tissues.149 Transforming growth factor-b3
mRNA and protein were not detected in any of the
studies.147149
Platelet-derived growth factor-A and PDGF-B
chain mRNA have been detected in cultured pleural
and peritoneal mesothelial cells,152154 although the
level of B chain mRNA was much lower than for the A
chain.152 Langerak et al.153 found that the B chain was
only expressed following spontaneous transformation in vitro of a normal mesothelial cell line, consistent with high levels of PDGF-B chain found in
malignant mesothelioma cell lines.152,155 Mesothelial
cells also constitutively express mRNA for the
heparin-binding growth factors, basic FGF (bFGF),
HB-FGF and VEGF50,156158 and, upon stimulation with
IL-1 and TNF-a, increase their mRNA and protein
levels for HB-EGF and VEGF, but not bFGF.156
However, IL-2 produced a marked suppression in HBEGF and bFGF, but not VEGF, mRNA expression.156
Cronauer et al.159 showed constitutive bFGF protein
in cultured human peritoneal mesothelial cells, predominantly intracellular, which increased following
IL-1 stimulation. This increase in intracellular bFGF
concentration was associated with an induction of
the release of bFGF and an increase in the steady state
levels of bFGF mRNA. Mesothelial VEGF production
also increased following exposure to TGF-b2 and
was inhibited in the presence of a TGF-b-blocking
antibody.158 Recently, mesothelial cells have been
shown to synthesize other growth mediators, such as
endothelin-1 and PAF following stimulation160 with
thrombin, hepatocyte growth factor (HGF)161,162 and
keratinocyte growth factor (KGF).161 Interestingly,
HGF and KGF are generally considered as epithelial
cell-derived growth factors, stimulating mesenchymal cell proliferation and migration. The finding that
mesothelial cells also express the receptors for these
factors confirms the dual epithelial/mesenchymal
properties characteristic of this cell.161,162

178
Mesothelial cells also respond to a host of other
cytokines and growth factors. Epidermal growth
factor, TGF-b1 and TGF-b2, PDGF, FGF, IL-1, TNF-a
and IFN-a,b,g are mitogenic for human mesothelial
cells in vitro and in vivo.163167 In addition, mesothelial cells are capable of proliferation and chemotaxis
in response to products of the coagulation cascade,
including thrombin168 and fibrinopeptides.169
Mesothelial cells also have the capacity to synthesize a variety of ECM macromolecules in vitro. Cultured rat mesothelial cells produce collagen types I,
III and IV, elastin, fibronectin and laminin.170175
Furthermore, electron microscopy studies reveal
that pleural mesothelial cells can organise these components into complex structures that resemble components of the ECM in vivo (thick collagen fibres,
the amorphous components of elastic fibres and
basement membrane-like structures), which were
restricted to the basal region below the cells in
culture.170 Several studies have also demonstrated
increased production of these molecules following
incubation of cells with various cytokines and growth
factors, such as TNF-a, EGF and PDGF.173,174,176 Interestingly, NO suppressed collagen production by
mesothelial cells, suggesting that NO may compromise the ability of the mesothelial cell to repair the
serosal tissue during conditions associated with significant pleural inflammation. Alternatively, NO may
prevent the excessive formation of fibrotic tissue.175
Cultured human pleural mesothelial cells synthesize large amounts of collagen types I and III, but no
evidence has been reported for collagen type IV.111,177
Incubation of human peritoneal mesothelial cells with
TGF-b increased mRNA expression for collagen type
III, but reduced expression for collagen type I. The
same results were obtained when cells were cultured
under hypoxic conditions.178 Mesothelial cells also
increase collagen synthesis following IL-1b treatment179 and exposure to peritoneal effluents obtained
from patients with acute peritonitis.180 Evidence from
these studies suggests that upregulation of ECM molecules by IL-1, hypoxia and factors present in infected
serosal effluents are likely to occur, at least in part,
through a TGF-b-dependent mechanism. It is likely
that overexpression of TGF-b in serosal tissues can
lead to fibrosis and adhesion formation. It is possible
that mesothelial cells regulate TGF-b activity by secreting the TGF-b inhibitors, decorin and biglycan.181
Mesothelial cells are also likely to play an important role in regulating the ECM turnover that
follows serosal injury by secreting metalloproteinases
(MMP) and tissue inhibitors of metalloproteinases
(TIMP).182184 It has been proposed that the state of
differentiation of these cells has a marked influence
on MMP and TIMP expression, such that cells with
an epitheloid morphology adopt a more ECMdegradative phenotype.182 Regulating the balance
of these molecules, together with the level of ECM
production, is important for the outcome of
injury, leading either to tissue regeneration and reestablishment of normal function or fibrosis and
adhesion formation.
Cell-to-cell and cell-to-ECM adhesion has roles
in embryonic development, maintenance of tissue

SE Mutsaers

architecture, inflammatory response, tumour metastases and tissue repair.146,185 The role of integrins in
the adhesion of mesothelial cells to ECM in response
to injury and their effects on cell function have
not been widely studied. Integrins are a family of
heterodimeric molecules, composed of an a-subunit
non-covalently associated with a b-subunit186 that
bind to ECM molecules. To date, at least 23 structurally distinct integrins have been described. Human
primary pleural mesothelial cells demonstrated high
expression of a2, a3, a5, b1, b3 and avb3 integrins,
with less expression of a1, a4 and a6.187 Functionally,
mediators, such as EGF, have been shown to stimulate a reversible change in mesothelial cells to a
fibroblastic phenotype that is accompanied by an
increased expression of b1 integrins, in particular
a2b1, facilitating enhanced adhesion to and migration on collagen type I.188 In addition, in response to
asbestos, integrins on rabbit pleural mesothelial cells
interact with specific ECM molecules causing cells
to change their shape and ability to internalize
asbestos.189 Plating human peritoneal mesothelial
cells on different ECM proteins also had a profound
effect on cell proliferation.190 These examples clearly
demonstrate that integrin expression on mesothelial
cells influences cell shape and behaviour. The role
of integrins in mesothelial cell function and repair
demands further study.

ANTIGEN PRESENTATION
Antigen presentation and T cell activation are the
first steps in the generation of a specific immune
response. Recognition of foreign antigens by Th
cells is dependent on their presentation by major
histocompatibility complex (MHC) class II molecules, which are expressed on professional antigenpresenting cells (APC), such as dendritic cells,
macrophages, monocytes and B cells.191 Other cells
normally do not express class II molecules, although
non-professional APC, such as endothelial cells
and keratinocytes, can express these molecules and
present antigen following cytokine stimulation.191,192
For cells to present antigen, there must be interaction
between the T cell receptor, class II molecules and
specific accessory molecules on the presenting cells,
such as B7-1 and B7-2. Intercellular adhesion molecule-1 can also act as an accessory molecule, usually
on non-professional APC.191,192
Valle et al.193 demonstrated that human peritoneal
mesothelial cells are able to present tetanus toxoid
and Candida albicans bodies to mononuclear cells
depleted of adherent cells and to a T cell clone.
In a similar study, Hausmann et al.141 generated
highly purified Th cells, depleted of B cells, dendritic
cells and monocytes. They demonstrated that, in
the absence of professional APC, human peritoneal
mesothelial cells stimulated by IFN-g effectively
induced the proliferation of CD4+ Th cells when the
antigen tetanus toxoid or the super antigen Staphylococcus aureus a toxin were present. High levels of
ICAM-1 were also detected on the mesothelial cell
surface following IFN-g treatment, whereas B7-1 and

Mesothelial cell: Structure and function

B7-2 molecules were not, suggesting that ICAM-1 is

the major accessory molecule for antigen presentation by mesothelial cells.141,193
Activation of mesothelial cells with IFN-g also
induced IL-15 production by mesothelial cells.141
Interleukin-15 is a pleotrophic cytokine with many
activities related to cell-mediated immunity, such as
stimulation of T cell growth.194 In addition, it has been
proposed that IL-15 cooperates with IL-2 in the initiation of an immune response and, subsequently,
enhances IL-2 responsiveness.195 Elevated levels of IL15141 and IFN-g196 were also found in the effluent of
patients suffering from peritonitis, suggesting that
IFN-g release from activated Th cells during peritonitis could induce peritoneal cells to produce IL-15.

TUMOUR GROW TH AND

DISSEMINATION
There have been very few studies examining the role
of the mesothelial cell in tumour growth and dissemination within serosal cavities. Most studies have concentrated on examining tumour recurrence following
surgery, clearly showing that traumatized mesothelial surfaces are privileged sites for tumour cell
adhesion.197 Van der Wal et al.198 suggested that this
was due to upregulation of adhesion molecules on
mesothelial cells in response to inflammatory mediators, thus promoting the anchoring of tumour cells
followed by growth promotion of the adhered tumour
cells through the action of locally produced growth
factors. Although mesothelial cells may play a role,
it is more likely that entrapment of tumour cells
in the fibrinous exudate deposited following trauma
and binding of tumour cells via integrins to exposed
submesothelial connective tissue are the main
mechanisms of attachment.199 However, as discussed,
mesothelial cells synthesize a host of growth factors
in response to inflammatory stimuli and, therefore,
may play a role in stimulating tumour growth.
Several experimental studies have demonstrated
that, following surgical trauma, tumour growth is
also enhanced at sites distal to the injury.200202 In
addition, increased tumour growth was observed in
animals exposed to surgical wound fluid or a combination of the growth factors TGF-b and bFGF,
suggesting that mediators produced after surgical
trauma enhance local and distant tumour growth.202
It is likely that these mediators induce upregulation
of cell adhesion molecules on mesothelial cells, promoting tumour cell attachment. Once the tumour
cells adhere to mesothelial cells, they can migrate
through the mesothelium, invade local organs and
move to distant sites. Interleukin-1b, TNF-a and
IFN-g upregulate adhesion molecule expression on
mesothelial cells138,139,141 and IL-1b and EGF increase
tumour cell adhesion to cultured mesothelial cells.140
Interestingly, incubation of mesothelial cells with
TNF-a had no effect on tumour cell attachment.140 In
the absence of surgical trauma, it is possible that the
tumours themselves secrete mediators that upregulate adhesion molecule expression on mesothelial
cells.

179
Numerous studies have demonstrated that adhesion of tumour cells to the hyaluronan pericellular
coat of mesothelial cells is an important step in
the peritoneal spread of ovarian and colorectal
cancer.86,203208 A wide variety of malignancies of
epithelial and mesenchymal origin express high
levels of the hyaluronan receptor CD44,209 although
the degree of adhesion does not necessarily relate
to the amount of CD44 expressed.204,205 This may
be due to differences in CD44 glycosylation205 or
variant forms of CD44.209 Blocking interaction of
CD44 with hyaluronan using antisense CD44 cDNA208
monoclonal antibodies that block the hyaluronanbinding site of CD44,86,203,205,207 intact hyaluronan and
hyaluronan oligomers,86 reduced cell adhesion and
inhibited cell migration. However, because blocking
CD44 did not totally inhibit mesothelial binding in all
studies, it is likely that other surface molecules are
involved.
The role of integrins in the interaction of tumour
cells with mesothelial cells has also been
explored.86,206,207 As well as synthesis of ECM molecules by mesothelial cells, damage to the mesothelium or rounding of mesothelial cells after
stimulation can expose underlying connective tissue.
Hepatocyte growth factor and TGF-b can both induce
rounding and separation of mesothelial cells, exposing submesothelial connective tissue.210,211 Lessan et
al.207 demonstrated that they could reduce adhesion
of an ovarian carcinoma cell line to mesothelial
cells by using a monoclonal antibody against the b1
integrin subunit, which is common to many integrin
molecules and can bind a variety of ECM proteins.
Migration of ovarian carcinoma cell lines towards
fibronectin, type IV collagen and laminin can be
blocked by antibodies against a5b1, a2b1 and a6b1,
respectively.86 Equally, antibodies against CD44
reduced cell adhesion and migration, suggesting that
tumour migration is regulated by both integrindependent and -independent mechanisms.
Although mesothelial cells appear to mainly
promote tumour dissemination and growth, intact
hyaluronan inhibits the adhesion of tumour cells
to mesothelium.86 Similarly, conditioned medium
from a confluent mesothelial cell culture containing
high amounts of hyaluronan prevented tumour cell
attachment to mesothelial cells, but hyaluronidase
treatment increased tumour cell adhesion.87 Free
hyaluronan in the conditioned medium would have
bound to the CD44 molecules on the tumour cells and
blocked their interaction with the hyaluronan present
on the surface of the mesothelial cells. Removal of free
hyaluronan may explain why tumour cells adhered
to mesothelial cells in other studies. Therefore,
under normal physiological conditions, secretion of
hyaluronan by mesothelial cells into the serosal fluid
may protect the serosal surface from tumour implantation. Following resection of peritoneal tumours,
many surgeons lavage the peritoneal cavity to remove
blood and other biological material. It is possible that
this practice is detrimental to the patient because
it actually provides residual tumour cells with a
favourable environment to attach and reseed onto
the serosal surface.

180

COAGUL ATION AND FIBRINOLYSIS

Mesothelial cells play an important role in local fibrin
deposition and clearance within serosal cavities.
Their fibrinolytic activity is a key factor in the prevention and removal of fibrin deposits that form
following mechanical injury, hemothoraces and
infection (Fig. 4). If the fibrinolytic capacity is insufficient and fibrin accumulation is not resolved, fibrous
adhesions form between opposing serosal surfaces.
In the peritoneum, adhesions occur in 93100% of
patients who have undergone abdominal surgery.212
These adhesions are the major cause of intestinal
obstruction,213 are responsible for up to 20% of infertility cases in women214 and are thought to cause
abdominal pain.215217 In the thorax, pleural loculation
and adhesions can impair lung function and cardiac
adhesions may have a deleterious effect on cardiac
function218 and/or result in decreased coronary artery
bypass graft patency.219 In addition, adhesions make
the growing number of repeat surgical procedures
difficult for the surgeon and hazardous for the
patient.
Mesothelial cells have both procoagulant and fibrinolytic activity. The procoagulant activity is due
to tissue factor, the main cellular initiator of the
extrinsic coagulation cascade,220 and assembly of the
prothrombinase complex at the mesothelial cell
surface.221223 Fibrin deposition is also aided by the
secretion of the plasminogen activator inhibitors
(PAI) PAI-1 and PAI-2.221,224228 The main plasminogen
activators (PA) are tissue PA (tPA) and urokinase PA
(uPA). The PA convert the inactive zymogen plasminogen into active plasmin, which, in turn, enzymatically breaks down fibrin.221,226,229 Mesothelial cells
are the main source of tPA in serosal cavities but
secrete lower levels of uPA.230
There is a fine balance between fibrin deposition
and breakdown in serosal cavities, which, if inappropriately regulated, can cause reduced fibrin clearance
and result in adhesion formation.231 Both pro- and
antifibrinolytic mediators are regulated by inflammatory factors, including LPS, TNF-a and IL-1,232235 and
fibrogenic mediators, such as TGF-b and throm-

Figure 4 Scanning electron micrograph of a serosal lesion

24 h after injury. A meshwork of fibrin (F) covers cell aggregates at the edge of the lesion. Bar, 5.26 mm.

SE Mutsaers

bin.227,236,237 These mediators reduce production of tPA

by mesothelial cells while increasing synthesis of PAI1, causing a significant delay in fibrinolysis. Transforming growth factor-b is also a potent inducer of
collagen production and has been used experimentally to induce pleurodesis in animal models.238,239
Redressing this imbalance by blocking PAI or the
mediators upregulating their synthesis may be a way
of preventing adhesions. This proposal is supported
by experimental studies in rodents, where it was
shown that blocking the activity of PAI-1240 or TGF-b241
with neutralizing antibodies had a significant effect
on reducing adhesion formation.240
There have been many reports describing materials, primarily barrier membranes and gels, that
reduce adhesion formation by separating serosal surfaces.242 However, these materials are not widely used
because of problems associated with their clinical
application and their limited success. It is widely
accepted that the future direction in preventing adhesions is through the application of growth factors and
mediators designed to increase the rate of serosal
repair and to break down fibrin. However, despite the
clinical importance of adhesions, there is little information available regarding the basic physiology of
serosal wound repair and adhesion formation and the
mediators regulating these processes.

MESOTHELIAL REGENERATION
The exact mechanisms involved in mesothelial regeneration are controversial. Hertzler, in 1919,243 was the
first to note that both large and small peritoneal
injuries healed at the same rate. He concluded from
this observation that mesothelium could not heal
solely by the centripetal migration of proliferating
cells at the wound edge into the injured area, as occurs
for healing of squamous epithelium. Since Hertzlers
early observations, many studies using different types
of serosal injury have been performed to elucidate the
mechanisms regulating mesothelial regeneration, following deep lacerations,67,244,245 broad abrasions,46,246
minor linear scarifications,247 drying,248 chemical
treatment249 and heat injury.2931,34,46,250 Based on these
studies, it is now generally accepted that the healing
process begins, within 24 h of injury, upon the arrival
at the wound surface of a population of round cells
and is completed 710 days later when the area is
covered by cells displaying all the characteristics of
mesothelial cells.2931,245,246 The origin of these new
mesothelial cells has not yet been confirmed, but a
number of possibilities have been proposed (Fig. 5),
including centripetal migration of mesothelial cells,
exfoliation of mature or proliferating mesothelial cells
from adjacent or opposing surfaces, which settle on
the wound surface and replicate, pre-existing freefloating serosal reserve cells that settle on the wound
surface and gradually differentiate into new mesothelium, macrophage transformation, submesothelial
mesenchymal precursors and bone marrow-derived
circulating precursors.

181

Mesothelial cell: Structure and function

Figure 5 Diagrammatic representation of the proposed

origins of regenerating mesothelium. (1) Centripetal migration of mesothelial cells; (2) exfoliation of mature or proliferating mesothelial cells from (a) adjacent or (b) opposing
surfaces; (3) pre-existing free-floating serosal reserve cells;
(4) transformation of serosal macrophages; (5) submesothelial mesenchymal precursors; and (6) bone marrowderived circulating precursors.

Figure 7 Scanning electron micrograph of a serosal lesion

48 h after injury. At the edge of the lesion, large flattened
mesothelial cells (M), with variable numbers of short fine
microvilli, have lamellopodia extended over fibrin and other
cells. Bar, 5.25 mm.

serosa from the edge of the wound to the centre

(Fig. 7). However, this does not explain how large and
small wounds can heal at the same time. It is clear
that simple migration of cells is not the only mechanism of regeneration.
Of the remaining proposals, irradiation29,30 and
cell labelling studies30,46,67,244246,252 have clearly shown
that macrophage transformation and a circulating
bone marrow-derived mesothelial precursor are
unlikely. Therefore, as well as migration of cells into
the wound from the edge of the lesion, regenerating
mesothelium is likely to originate either from a submesothelial mesenchymal precursor or free-floating
mesothelial cells.
Figure 6 Autoradiograph showing a surface imprint of a
[3H]-thymidine-labelled serosal lesion 48 h after injury. A
high density of proliferating cells (dark nuclei, small arrows)
is seen surrounding the lesion (L). The edge of the lesion is
defined by large arrows. Bar, 0.625 mm. Reproduced with
permission from Mutsaers et al.250

LOCAL CELL PROLIFERATION AND

CENTRIPETAL MIGRATION
The mesothelium is a slowly renewing tissue that can
be stimulated by a variety of agents and direct physical damage to increase its turnover rate. Watters
and Buck251 reported that apposing serosal surfaces
undergo maximal division 2 days after injury and
further demonstrated that both surfaces are triggered
simultaneously, suggesting that a stimulus may traverse the space between them. Subsequent kinetic
studies using [3H]-thymidine uptake as a marker
for DNA synthesis have demonstrated that 6080%
of mesothelial cells at the wound edge and on the
apposing surface are dividing 2448 h after injury29,250
(Fig. 6). There is no doubt that proliferating cells surrounding the wound play an important role in the
repair process, many migrating across the injured

SUBMESOTHELIAL MESENCHYMAL
PRECURSOR
It was proposed that, upon appropriate stimulation,
subserosal connective tissue fibroblast-like cells
migrated to the serosal surface and differentiated into
mature mesothelial cells.244,245,252 This proposal was
supported by embryology and cell culture studies that
demonstrated that mesothelial cells can modulate
their morphology under different conditions and
display many of the characteristics associated with
fibroblasts, such as ECM production.174,175,177,179,207,253
Furthermore, Bolen et al.,254,255 examining intermediate filament expression in serosal tissues from
human pathologies, demonstrated that some submesothelial fibroblast-like cells expressed cytokeratins, a
feature characteristic of epithelial and mesothelial
cells, but not normally expressed by fibroblasts. These
results were interpreted to suggest that submesothelial spindle cells are multipotential and have the
capacity to differentiate into surface mesothelial
cells. Whitaker et al.,256 in a similar study, were unable
to reproduce these findings and suggested that the
staining pattern seen by Bolen et al. may not be a
result of submesothelial cells differentiating into
surface mesothelial cells but, instead, may be due

182
to mature mesothelial cells migrating into the subserosal connective tissue.
Although the proposal of a multipotential submesothelial precursor for regenerating mesothelial cells
has generally been favoured, substantial evidence
against such a theory exists.29,250,257259 Implantation of
polyethylene sheeting onto denuded serosa did not
prevent remesothelialization.257 A mesothelial membrane was grown from free serosal cells by using a
diffusion chamber placed in the peritoneal cavity
of rats, ensuring no possible contact with fibroblastlike cells.258 Irradiation studies have demonstrated
impaired local mesothelial regeneration, which was
recoverable by addition of peritoneal lavage cells.29 In
addition, a kinetic study of serosal repair demonstrated that subserosal cells were not essential for
mesothelial healing and that the regenerating cells
were likely to originate from the surrounding uninjured serosal surface.250

FREE-FLOATING MESOTHELIAL CELLS

In 1957, Cameron et al.247 proposed that mesothelial
healing involved attachment of free-floating mesothelial cells to the injured surface. Peritoneal lavage fluid
recovered from experimental animals following injury
to the mesothelium was found to contain a significantly increased number of viable free-floating
mesothelial cells, 2 days post-injury compared with
controls.29 The increased free-floating cell population
was thought to be due to proliferation of mesothelial
cells adjacent to250,257 and opposing30,260 the serosal
injury. Further support for this proposal came from
implantation of polyethylene sheets and diffusion
chamber studies, as described previously, demonstrating that reconstitution of the mesothelium could
occur without contact with submesothelial fibroblastlike cells.257,258 Furthermore, Cleaver et al.261 showed
that the healing rate of the mesothelium was retarded
following postoperative peritoneal lavages, possibly
due to the removal of the free-floating serosal cells.
Replacement of these cells in irradiated animals
resulted in a marked increase in the healing rate of the
testicular mesothelium.29
The most compelling evidence to support a freefloating origin for regenerating mesothelium is
from recent in vivo cell-tracking studies.46 Cultured
mesothelial cells, peritoneal lavage cells and control
fibroblasts were labelled with a tracking dye (1,1dioctadecyl-3,3,3,3-tetramethylindo-carbacyanine
perchlorate; DiI) and injected into rats immediately
following mesothelial injury. Labelled cultured
mesothelial and peritoneal lavage cells, but not cultured fibroblasts, implanted onto the wound surface
and began to proliferate. By examining ZO-1 expression in the regenerating mesothelium, it was also
shown that the DiI-labelled cells began to form
junctional complexes, clearly indicating that implanted cells were incorporated into the regenerated
mesothelium.
From these findings and those of others, a model
of mesothelial repair was proposed.46 Mesothelial

SE Mutsaers

regeneration requires recruitment of inflammatory

cells to the wound surface and release of mediators to
activate and stimulate mesothelial cell proliferation
surrounding the wound.30,31 Activated mesothelial
cells break their cell-to-cell contacts and migrate onto
the wound surface,29 possibly through the action of
HGF, which is secreted by mesothelial cells161,162,262
and surrounding fibroblasts.210 A population of
mesothelial cells adjacent to the wound and on the
apposing surface detach and become free floating,29
move along chemotactic gradients and attach to ECM
components exposed beneath the mesothelium or
deposited from the serosal fluid, proliferate and
reconstitute an intact mesothelial monolayer.

SUMMARY AND CONCLUSIONS

The mesothelium was first described 175 years ago,
but it has only been in the past 20 years that we have
started to appreciate the roles that mesothelial cells
and the mesothelium play in maintaining normal
serosal membrane integrity and function. Mesothelial cells are biologically active cells that can sense and
respond to signals within their microenvironment.
They secrete glycosaminoglycans and surfactant to
provide a frictionless free surface between parietal
and visceral serosa. They actively transport fluids and
particulates across the serosal membrane and form
openings or stomata, directing movement of cells to
and from the serosal cavities. Mesothelial cells can
synthesize and secrete a diverse array of mediators in
response to external signals, initiating and regulating
an inflammatory response, recruiting cells into the
serosal cavities and presenting antigen to T cells. They
also play an active role in tissue repair through the
release of growth factors and ECM molecules and
their protease and fibrinolytic properties are of major
importance in preventing fibrosis and the formation
of adhesions. In addition, secretion of hyaluronan
into serosal fluids may play an important role in preventing the dissemination and growth of tumours.
Despite the realization that the mesothelium is
not merely a protective slippery barrier there are still
many questions that remain unanswered. Mesothelial cells can clearly regulate the influx of inflammatory cells into serosal cavities upon stimulation, but
their role in cell clearance during the resolution of
inflammation has not been examined. Stomata have
been identified in the mesothelial membrane, but
nothing is known about how mesothelial cells and
lymphatic endothelium communicate to form these
openings. It is possible that mesothelial cells act in
concert with underlying fibroblast-like cells to ensure
serosal integrity, but the relationship between these
cells is unclear. It has been proposed that adhesion
formation between serosal tissues occurs because
damage to the mesothelium reduces the fibrinolytic
capacity of the serosal membranes. No one has
started to examine the role mesothelial cells may
actively play in the formation of adhesions. Mesothelial cells are able to change between epithelial and
fibroblastic phenotypes. Identifying the genes regulating this transformation may provide some insight

Mesothelial cell: Structure and function

into the development of the different histogenic

forms of malignant mesothelioma.
Regeneration of the mesothelium is unlike other
epithelial-like surfaces because healing does not
occur solely by centripetal migration of cells from the
wound edge. The mechanism of repair is controversial, but recent evidence suggests that free-floating
mesothelial cells implant, proliferate and incorporate
into the regenerating mesothelium. Before this proposal is fully accepted, many questions must first be
answered. For example, the mechanisms by which
these cells break cellcell contacts and become
detached from the basement membrane are not
known, although regulation of integrins or proteolytic
dissociation of ECM may be involved. We do not
understand what signalling mechanisms allow the
free-floating cells to remain viable in the serosal fluid
and not undergo apoptosis. It is not clear what directs
the free-floating cells to the injured site and allows
them to attach and migrate on the wound surface.
In addition, and possibly most importantly, we need
to understand more about the nature of the freefloating cell population and determine whether
these are just desquamated mesothelial cells or a
dedicated precursor cell population.
The present review has highlighted some of our
current knowledge on the structure and function of
mesothelial cells in maintaining tissue homeostasis
and their role in repair. However, many questions still
need to be answered before we can begin to understand the pathogenesis of serosal pathologies, such as
pleural loculations, adhesion formation and malignant mesothelioma.

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