The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642


Mesothelial progenitor cells and their potential in tissue engineering
Sarah E. Herrick a,∗ , Steven E. Mutsaers b
a b

School of Biological Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK Asthma & Allergy Research Institute, Department of Medicine, University of Western Australia, Nedlands, Australia Received 16 September 2003; received in revised form 3 November 2003; accepted 4 November 2003

Abstract The mesothelium consists of a single layer of flattened mesothelial cells that lines serosal cavities and the majority of internal organs, playing important roles in maintaining normal serosal integrity and function. A mesothelial ‘stem’ cell has not been identified, but evidence from numerous studies suggests that a progenitor mesothelial cell exists. Although mesothelial cells are of a mesodermal origin, they express characteristics of both epithelial and mesenchymal phenotypes. In addition, following injury, new mesothelium regenerates via centripetal ingrowth of cells from the wound edge and from a free-floating population of cells present in the serosal fluid, the origin of which is currently unknown. Recent findings have shown that mesothelial cells can undergo an epithelial to mesenchymal transition, and transform into myofibroblasts and possibly smooth muscle cells, suggesting plasticity in nature. Further evidence for a mesothelial progenitor comes from tissue engineering applications where mesothelial cells seeded onto tubular constructs have been used to generate vascular replacements and grafts to bridge transected nerve fibres. These findings suggest that mesothelial cell progenitors are able to switch between different cell phenotypes depending on the local environment. However, only by performing detailed investigations involving selective cell isolation, clonal analysis together with cell labelling and tracking studies, will we begin to determine the true existence of a mesothelial stem cell. © 2003 Elsevier Ltd. All rights reserved.
Keywords: Peritoneum; Stem cells; Epithelial-mesenchymal transitions; Adhesions; Serosa

Contents 1. 2. 3. 4. 5. 6. 7. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryology and morphology of mesothelial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functions of the mesothelial cell layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mesothelial healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adhesion formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence for a multipotential subserosal mesenchymal cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epithelial-mesenchymal transition of mesothelial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622 622 623 625 627 628 629

Corresponding author. Tel.: +44-161-275-6765; fax: +44-161-275-5945. E-mail address: (S.E. Herrick).

1357-2725/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2003.11.002


S.E. Herrick, S.E. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642

Tissue engineering potential of mesothelial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Vascular grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Omental grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Nerve grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Does a mesothelial ‘stem’ cell exist? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.

631 631 632 633 634 636 636 636

1. Introduction The mesothelium lines the peritoneal, pleural and pericardial cavities with visceral and parietal surfaces covering the internal organs and body wall, respectively. It comprises a monolayer of epithelial-like cells resting on a thin basement membrane supported by sub-serosal connective tissue containing blood vessels, lymphatics, resident inflammatory cells and fibroblast-like cells (Wang, 1974; Ishihara et al., 1980; Albertine, Wiener-Kronish, Roos, & Staub, 1982). The sole function of the mesothelial layer was traditionally thought to provide a protective, non-adhesive surface to facilitate intracoelomic movement. However, it is now recognised as a dynamic cellular membrane with many physiological functions including the control of fluid and solute transport, immune surveillance and the production of extracellular matrix (ECM) molecules, proteases, cytokines and growth factors. The mesothelium is bathed in serosal fluid that resembles an ultrafiltrate of plasma and contains blood proteins, resident inflammatory cells, sugars and various enzymes including amylase and lactate dehydrogenase (Dondelinger, Boverie, & Cornet, 1982). The composition and volume of the serosal fluid is indicative of certain pathological states, such as peritonitis, tumorgenesis and endometriosis (Haney, 1993), and it is likely that the mesothelial layer responds as a single unit to changes in serosal fluid composition. Indeed, repair of serosal tissue involves increased mesothelial cell proliferation at sites distant to the wound, suggesting diffuse activation of the mesothelium in response to mediators or cells released into the serosal fluid, or via cell to cell communication (Mutsaers, McAnulty et al., 1997; Mutsaers, Whitaker, & Papadimitriou, 2002). Although local proliferation of resident cells surrounding a lesion is one source of healing cells, recent

reports suggest that the repair of many organs in the adult organism also involves incorporation of multipotential stem cells and as such, has generated exciting prospects in cell and tissue engineering (Bianco & Robey, 2001; Goodell, 2001; Tuan, Boland, & Tuli, 2003). A rich reservoir of these cells resides in specific niches within the bone marrow microenvironment as well as in a variety of connective tissues where they are maintained in an undifferentiated and quiescent state. At present, there is a lack of a unifying definition that characterises cells as stem cells. However, a general definition is a cell capable of extensive self-renewal that can give rise to successively more differentiated progeny cells (Wagers, Christensen, & Weissman, 2002). Although a ‘classic’ mesothelial stem cell has not been identified, many lines of evidence suggest that a mesothelial progenitor cell does exist. This review will describe the mesothelial cell in terms of its embryological origin, morphological characteristics and diverse functions. Subsequent sections present evidence to support the concept of a free-floating mesothelial ‘progenitor’ cell present in serosal fluid and also discuss mesothelial cell differentiation, novel tissue engineering applications for these cells and possible future research directions in this rapidly developing field.

2. Embryology and morphology of mesothelial cells Bichart, in 1827 (reviewed by Whitaker, Papadimitriou, & Walters, 1982a) first observed that serous cavities were lined by a layer of flattened cells similar to those of the lymphatics. Minot (1890) subsequently proposed the term ‘mesothelium’ following a detailed study of its embryological origin that showed this layer to be the ‘epithelial lining of mammalian mesodermic cavities’. It is now understood that during human

The somatic mesoderm and overlying embryonic ectoderm form the embryonic body wall (somatopleure). 1998). Ultrastructural analysis of polarised mesothelial cells demonstrates well developed cell–cell junctional complexes including tight Fig. a plaque protein associated with tight junctions. They also express E-. The lateral mesoderm is continuous with the extraembryonic mesoderm covering the yolk sac and amnion. Morphologically. Mesothelial cells display many epithelial characteristics including a polygonal cell shape. 1). squamous-like and cuboidal. intermediate and lateral mesoderm. whereas the splanchnic mesoderm and embryonic endoderm form the embryonic gut wall (splanchnopleure). Robinson. alpha smooth muscle actin (Afify. Between 5 and 7 weeks. but share characteristics of both epithelial and mesenchymal cells (Whitaker. 1999). In this phase of development. and together as serous membranes (reviewed by Thors and Drukker. In particular. Mehta. Although mainly squamous in appearance. Monolayer imprint of normal rat peritoneal mesothelial cells showing immunoreactivity for zonula occludens-1 expression. Baradi & Rao. Bar. (2002). dividing the mesoderm into two layers: the intraembryonic somatic or parietal layer and the intraembryonic splanchnic or visceral layer. 8. suggesting a more metabolically active state (Kluge & Hovig. S. N. Manning. 1963. spleen). Paulino. the ‘milky spots’ of the omentum. desmin and upon stimulation. non-adhesive epithelial surface. 1992). length and density between adjacent cells and between different organs (Mutsaers. 3. & Davila. & Franke. At the end of week 3. N-cadherin predominates (Simsir... 1974). microtubules and a greater number of microfilaments compared with squamous cells.E.E. & Papadimitriou. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 623 development. Fetsch. Functions of the mesothelial cell layer As well as providing a slippery. 1996). Reproduced with permission from Foley-Comer et al. 1982a. Whitaker & Papadimitriou. & Walters. In their fully differentiated state. The microvilli vary in shape.b. and peritoneum respectively. cuboidal cells have abundant mitochondria and rough endoplasmic reticulum (RER). cuboidal mesothelial cells also exist at various locations including septal folds of the mediastinal pleura. parenchymal organs (liver. Moll. the coelom is sub-divided by a process of septation into a future pericardial cavity. cytokeratin intermediate filaments (cytokeratins 6. the intraembryonic mesoderm on each side of the neural groove differentiates into paraxial. Zakowski. gap junctions and desmosomes (Pelin. Whitaker. They also predominate following injury or stimulation of the serosal surface (Mutsaers et al. The two forms of mesothelial cell. small spaces appear in the lateral mesoderm that fuse.S. Levy. junctions (zonula occludens) located towards their luminal aspect. two pleural cavities and a peritoneal cavity. 1. and the peritoneal side of the diaphragm overlying the lymphatic lacunae (Wang. the mesothelial layer performs many . & Abati. they also show features of mesenchymal cells such as the presence of vimentin. Papadimitriou. the mesothelial and submesothelial layers of the coelom are referred to as the pericardium. A continuous mesothelial membrane lines the margin of these two layers and so borders the intraembryonic coelom. and the ability to secrete a basement membrane. However. 1980). 1997). 18 and 19) (Czernobilsky. Hirvonen. 1985). & Shilkin. 1994) (Fig. localised to the plasma membrane. Fukata. 2002).and P-cadherins. but unlike true epithelia. with characteristic surface microvilli and occasional cilia. 1976. Mesothelial cells are therefore of a primitive mesodermal origin. also show differences ultrastructurally. a well developed Golgi apparatus. 1967. & Linnainmaa. 1985). they form a monolayer of predominantly squamous-like cells approximately 25 ␮m in diameter. Al-Khafaji. mesothelial cells are considered generally similar at different serosal sites and between different mammalian species (Whitaker et al. Baradi & Campbell. 10 ␮m. 2002. adherens junctions. Whitaker. Herrick. pleura.

2001). III. These include transport and movement of fluid and particulate material across serosal cavities.. Ramsey.. Mandl-Weber.and immunomodulatory mediators. Transforming growth factor-␤ (TGF-␤). This tumour.. Whitaker et al. Offner et al. is particularly aggressive and largely unresponsive to conventional chemotherapy or radiotherapy. In particular. differentiation and migration of mesothelial and submesothelial cells surrounding a lesion. prostacyclin and IL-6 (Topley et al. 2001). 2000. elastin. proteoglycans including syndecans and biglycan. fibronectin and laminin and regulate turnover through the production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Haslinger..b). 1998).. Jayne. and surfactant lubricants. and by changing microvilli density and adhesion molecule expression. 2002). Mesothelial cells also produce a multitude of cytokines and growth factors which can regulate inflammatory responses and stimulate tissue repair. A similar variability in phenotypic differentiation is observed in human and rodent malignant mesothelioma (Dobra.. platelet-derived growth factor (PDGF). lymphocytes and eosinophils to the site of challenge (Mutsaers.. which recruit neutrophils. Perry. increase the production of chemokines by mesothelial cells so potentiates the inflammatory response (Betjes et al. Furthermore. 1998. Endogenous IL-6 plays a crucial role in local and systemic acute inflammatory responses by controlling the levels of pro-inflammatory. Bishop. Herrick. Syrokou. McGrouther. hepatocyte growth factor (HGF). the enzymatic profile of squamous and cuboidal mesothelial cells suggests that the former fully differentiated state is involved with membrane transport whereas cuboidal mesothelial cells have a wider spectrum of activity (Whitaker et al. 1992.E. the sarcomatous growth pattern .E. Bryant. It has been proposed that the phenotypic state of the cells has a marked influence on MMP and TIMP expression so that cells with a squamous epithelioid morphology adopt an ECM-degradative phenotype whilst cuboidal cells deposit more matrix components (Marshall et al. 1994). Mesothelial cells secrete glycosaminoglycans (GAGs). 1970. IL-8. Bakowska. Mesothelial cells also release growth factors which initiate cell proliferation. 1980. Karamanos. in particular hyaluronan. Bellingan et al. and antigen presentation. 1982a. mesothelial cells also secrete anti-inflammatory mediators including prostaglandins. & McCluskey. anti. regulation of leucocyte migration in response to inflammatory mediators. interferon-␥ (IFN-␥)-inducible protein 10 (IP-10). 2000). RANTES.. 1993. KGF and HGF are generally considered as epithelial cell-derived growth factors that stimulate mesenchymal cell proliferation and migration... 2000. growth factors and ECM molecules. Andang. 1997. 1976. Adamson. monocyte chemoattractant protein-1 (MCP-1). monocytes. Stimuli such as bacterial products. 2000. and IV. Langerak et al. Tweeddale. Warn et al. synthesis of pro-inflammatory cytokines. 2001). growth-related oncogene-␣ (GRO-␣). Mesothelial cells also have the capacity to synthesise a variety of ECM macromolecules in vitro.624 S.. & Laurent. predominantly of the pleura. & Hjerpe. such as collagen types I.. 2000. Interestingly. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 diverse functions which are important in the maintenance of serosal homeostasis. tumour necrosis factor-␣ (TNF-␣) and IFN-␥. infection and possibly tumour dissemination. & Prieditis. However. Further stimulation by hyaluronan secreted by mesothelial cells. to regulate the inflammatory response.. 1993. Mutsaers. S. Raftery. These functions are often linked to the phenotypic state of the cell. in particular intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). to provide a slippery non-adhesive surface which also protects the serosal surface from abrasion. they can regulate trafficking of leucocytes into and out of serosal cavities (Liang & Sasaki. keratinocyte growth factor (KGF) and members of the epidermal growth factor (EGF) family are some of the factors likely to regulate these processes (Martin. & Guillou. 1996. & Sitter. Morrison. Sellmayer. asbestos. and products released from activated macrophages such as IL-1␤. 1993). stromal cell-derived factor-1 (SCD-1) and eotaxin. instilled agents and tissue injury induces release of pro-inflammatory cytokines and chemokines including interleukin (IL)-1. Farmery. 1996. The finding that mesothelial cells also express the receptors for these factors and can respond to them confirms the dual epithelial/mesenchymal properties characteristic of this cell type (Adamson et al. control of coagulation and fibrinolysis. fibroblast growth factor (FGF). For instance. Hopkinson-Woolley. they participate in serosal inflammation by secreting various pro-. & Braunstein. Warn et al. but not anti-inflammatory cytokines (Xing et al. Visser et al. 2002).

However. 2000.S. there is a fine balance between these processes.E. many studies involving a wide range of experimental model systems have been performed to elucidate the mechanisms regulating the regeneration process. binding via integrins to exposed submesothelial connective tissue is likely to be the main mechanism of attachment (Sugarbaker. TGF-␤ and FGF. Harada et al. For a more extensive review of mesothelial cell function see Mutsaers (2002). Oegema. but this inhibition was overcome following hyaluronidase treatment (Jones et al. Siebenson. If there is insufficient serosal fibrinolytic activity. It is likely that free hyaluronan in the conditioned medium bound to CD44 on the tumour cells and prevented them from binding to hyaluronan on the mesothelial cell surface. enhance local and distal tumour growth (Hofer et al. Hoekstra. It has been clearly shown that traumatised mesothelial surfaces are privileged sites for tumour cell adhesion (Cunliffe & Sugarbaker. S. bands of fibrous tissue that occur in up to 95% of patients following surgery. It has been suggested that this occurs due to upregulation of adhesion molecules on mesothelial cells in response to inflammatory mediators. 2000). there is much controversy regarding the mechanisms involved in normal serosal repair. which if disrupted may result in the formation of adhesions. Reichner. Catterall. He concluded that the mesothelium could not regenerate solely by proliferation and centripetal migration of cells at the wound edge as occurs for the healing of epithelium. 2002). it is proposed that adhesions develop if regeneration of the mesothelial layer is impaired. Mesothelial cells have also been implicated in both the spread and inhibition of tumour growth within serosal cavities. demonstrates an importance in regulating haemostasis and fibrin clearance (Sitter et al.. 2000. Removal of free hyaluronan may explain why tumour cells adhered to mesothelial cells in other studies.. Jones. evidence also suggests that secretion of hyaluronan by mesothelial cells into the serosal fluid may inhibit tumour cell adhesion (Casey & Skubitz. Mesothelial healing Hertzler (1919) was the first to observe that small and large peritoneal wounds healed in the same amount of time. 1998). 1998). 1999). Mesothelial cells at the wound edge undergo cell division and the epithelial . 2001. 1995). & Wanebo. 4. & Turner. 1999. 1993). Herrick. Animal studies demonstrated that tumour growth was increased following exposure to surgical wound fluid or a combination of the growth factors. as well as fibrinolytic mediators including the plasminogen activators (PA) urokinase PA (uPA) and tissue PA (tPA) by the mesothelium. 1997). This may occur by stimulating tumour cell proliferation but also through upregulation of cell adhesion molecules on mesothelial cells promoting their attachment and invasion into serosal tissues.. Adhesions initially form as fibrin-rich deposits between damaged. in particular the cells involved in the regeneration of the mesothelium. predominantly neutrophils and macrophages. 1995). Many studies have demonstrated that adhesion of tumour cells to hyaluronan bound to mesothelial cells is important for the spread of ovarian and colorectal tumours (Casey & Skubitz. on the wound surface (Mutsaers et al. these fibrin-rich adhesions persist. 1989). Although the pathophysiology of adhesion formation is poorly understood. Lessan. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 625 has been associated with a worse prognosis and may represent a less differentiated tumour (Fusco et al. However. Tumour growth is then potentiated by growth factors released from activated mesothelial cells.. become organised by invading fibroblasts and endothelial cells and with subsequent collagen deposition form permanent fibrous adhesions within a week of injury (Sulaiman et al.E. Catterall. Since then. It is generally agreed that the healing process begins within 24 h of injury with the appearance of a population of rounded cells. & Turner.. Aguiar.. 1995). 1991). However. The secretion of pro-coagulants such as tissue factor and fibrin stabilisers plasminogen activator inhibitor (PAI)-1 and -2. Several studies have also shown that following surgical trauma. tumour growth is also increased at sites distal to the injury (Hofer. Shrayer. Jones. promoting tumour cell adhesion (van der Wal et al. & Skubitz. Gardner.. Conditioned medium from confluent mesothelial cell cultures containing large amounts of hyaluronan prevented tumour cell attachment. closely opposed serosal surfaces. Following serosal injury. suggesting that mediators produced after surgical trauma or by the tumour cells themselves..

2002). Herrick.25% basal mitotic activity. many of which are inflammatory cells.E.626 S. kinetic studies using [3 H]-thymidine incorporation in rodent models confirmed that 28–60% of mesothelial cells at the wound edge and on the opposing surface were dividing 24–48 h after injury (Fig. Bar.. which upon stimulation by the exogenous addition of peritoneal inflammatory lavage cells and activated macrophages. 2000). Under normal conditions.. 1964.. 1962. they can be stimulated to divide by a variety of agents as well as by direct physical damage. S. Later. few mesothelial cells surrounding the wound are undergoing division. 1985. the majority of dividing cells are at the wound centre and are characterised as mesothelial cells. Fotev et al. 2000. such as HGF. 1985. Mutsaers et al.. Reproduced with permission from Mutsaers et al. Whitaker. Monolayer imprint of tritiated thymidine treated murine serosal lesions at (A) 24 h. Fotev. & Papadimitriou. it is likely that they play a significant role in inducing mesothelial cell proliferation and stimulating serosal repair. 2) (Whitaker & Papadimitriou. McAnulty et al. is identified by a high density of cells. 1987). Mutsaers. Johnson & Whitting. 1997) and chemotactic factors. At 4 days. Irrespective of the size of the damaged wound area. However.E. serosal healing is Fig. The centre of the lesion (c). (B) 2 days and (C) 4 days after injury. 125 ␮m. At 24 h. Whitaker. (2000). As inflammatory cells collect on the wound surface within the first 24 h of injury. the mesothelium is a slowly renewing tissue with 0. Bridges & Whitting. type of trauma or animal species. the margin between the centre and edge of the lesion defined by thick arrows. Watters and Buck (1973) showed that mesothelial cells on opposing serosal surfaces undergo maximal division 2 days after in- jury. . increased to values greater than 12% (Mutsaers et al. 2. & Papadimitriou. Dark nuclei are labelled with silver grains (small arrows) and represent cells undergoing division. 1987).5% of cells undergoing mitosis at any one time (Mutsaers et al. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 sheet temporally transforms into spindle-shaped fibroblastic cells that migrate onto the denuded wound area (Whitaker & Papadimitriou. We have shown that proliferative factors (Mutsaers.16–0. 2001). By 2 days approximately 28% of these cells are dividing. Our subsequent studies showed that uninjured murine testicular mesothelium has a 0. 2000... are likely to play a major role in stimulating this repair process (Warn et al.

. 1973). This suggests that free-floating mesothelial cells are able to adhere to exposed and deposited ECM substrates such as collagen. pre-existing free-floating serosal progenitor cells that implant on the wound and differentiate into mesothelial cells (Ryan et al. & Tugh. We found that both cultured and lavage-derived mesothelial cells implanted onto a peritoneal wound surface and underwent cell division with subsequent incorporation into the regenerating mesothelium as demonstrated by cell junction formation.E. 1957.E. Watters & Buck. 1972). extensive experimental evidence suggests that a free-floating serosal progenitor is probably involved.. and bone marrow-derived circulating precursors (Wagner. 1985. Bellingan. Cameron. 2000. 1987). Fotev et al. Grobety. Moreover. 1985. Hopkins. Venables. 1986.. A detailed histological and ultrastructural study of human peritoneal adhesions demonstrated that they were all well vascularised and innervated and contained clusters of smooth muscle cells. Teranishi. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 627 complete within 7–10 days of injury when the wound area is covered by cells displaying all the characteristics of mesothelial cells (Mutsaers et al. which are proteases essential to the fibrinolytic pathway (Sitter et al. Davila & Crouch. 1973). S. 2002. vitronectin and possibly fibrin following injury. 1973. exfoliation of mature or proliferating mesothelial cells from adjacent or opposing serosal surfaces (Whitaker & Papadimitriou. 2001).. 1993). cell depletion studies using whole body X-irradiation (Whitaker & Papadimitriou. & McNutt. 2002). chronic pain and infertility in women. Our own group has performed cell-tracking and labelling studies in rodent models and conclusively shown that serosal healing involves the incorporation and proliferation of free-floating mesothelial cells (Foley-Comer et al. Raftery. mesothelial cells are the major source of PA. 2002). Bolen.. undergo cell division and integrate into the mesothelial layer. Sulaiman. Nevertheless. Sulaiman et al. & Raftery (1974) showed that the healing rate of mesothelium was retarded following post-operative peritoneal lavages. Two major therapeutic approaches have been investigated to prevent adhesion formation: fibrinolytic . Peritoneal macrophages also attached to injured areas but failed to incorporate whereas peritoneal fibroblasts failed to attach. & Majno. & Herrick.. Based on this evidence. Harrison. Ryan. 1967) do not appear to support the claim that a bone marrow-derived precursor is involved in mesothelial healing. 1982). & Itaya. fibronectin. subserosal mesenchymal precursors that convert into mesothelial cells and migrate to the wound surface (Raftery. Whitaker & Papadimitriou. possibly due to the removal of the free-floating serosal cells. Ellis. there is a reduction in local PA secretion which reduces fibrinolytic activity. However. Hammar. & Burns. 1973. These include: macrophage transformation (Eskeland & Kjaerheim. Laurent.. Johnson & Whitting. studies have demonstrated that mesothelial regeneration is impaired following selective irradiation at the site of injury but recoverable after the addition of peritoneal lavage cells (Whitaker & Papadimitriou. & De. Mutsaers et al. If mesothelial healing is impaired. 1985. It is unlikely that the processes of cell division and migration alone account for these similar healing times. Herrick. 1995). 1962. It has been proposed that adhesions form as a consequence of reduced fibrinolytic activity in serosal tissues. 1977). but this finding still needs to be confirmed. Adhesion formation Adhesions are a common consequence of serosal injury in all three serosal cavities leading to serious complications such as intestinal obstruction. Further evidence for a free-floating progenitor arises from peritoneal fluid studies where a significantly higher number of viable free-floating mesothelial cells were recovered from experimental animals 2 days following injury compared with the control uninjured animals (Whitaker & Papadimitriou. 5. 1966. Brown. The origin of these regenerating cells is highly controversial. 1985). 1997. 1987. 2000.S. Ng Nee Kwong. Johnson.. 1985. For instance.. Ellis. It is not known whether these free-floating cells are desquamated mesothelial cells from the serosal lining. Dawson. Fotev et al. Cleaver. Sakaguchi. as did mesothelial cells to uninjured areas. 1965.. a number of groups have proposed additional sources for the regenerating mesothelial cells. a resident peritoneal fluid sub-population or a dedicated circulating precursor cell population. & Wagner. This has been shown both in human studies and genetically modified mouse models (Holmdahl et al. the origin of which was unclear (Herrick et al. In serosal tissue. Hassan.

It is assumed from these studies that the addition of exogenous mesothelial cells increased serosal repair so prevented adhesion formation. The future direction in preventing adhesions is likely to be the application of growth factors and mediators designed to increase the rate of serosal repair and so re-establish the tissue’s normal fibrinolytic capacity. In a rat surgical model. and Young (1996). (1990) found that intraperitoneal (i. immediately following surgical injury or at 4–6 h post-surgery. systemic fibrinolysis. the MSCs produce factors that inhibit the formation of the initial fibrin-rich adhesions. The authors proposed that MSCs have the capacity to differentiate into mesothelial cells capable of repopulating injured serosa and so prevent adhesion formation. four uremic peritoneal dialysis patients recovering from severe peritonitis were injected i. or if their differentiation state changes during culture or when introduced back into the peritoneal cavity. & Sacchi.E. although this has not been confirmed. due to complications associated with bleeding.. 2002). they also raise a number of important questions. These findings again support the concept that a free-floating progenitor mesothelial cell is involved in mesothelial repair however. 1991). Another approach to increase the rate of serosal repair is through the exogenous addition of mesothelial cells.p. there were morphological signs of cell incorporation in peritoneal biopsies suggesting this technique may have important applications for the prevention of adhesions in humans (Di Paolo et al. produced collagen and formed stronger and more extensive adhesions.p. Herrick. S. They compared the implantation of different concentrations of MSCs with dead MSCs or smooth muscle cells isolated from adult animals. Furthermore... In a clinical study by the same group. However. At laparoscopy 3 and 6 days post-implantation.p. Several groups have demonstrated that instillation of autologous mesothelial cells at the time of injury prevents adhesion formation (Di Paolo. Alternatively. Cells injected 4–6 h after injury are likely to have been trapped within deposited fibrin and may have differentiated into fibroblasts rather than mesothelial cells. 1999). Newman. Zhang. Adhesion number was significantly reduced in the animals receiving living MSCs at the time of surgery in a concentration dependent manner. Di Paolo et al. Bertram et al. 1990. For example. Evidence for a multipotential subserosal mesenchymal cell Another popular theory as to the origin of the regenerating mesothelial cells is that they are derived from multipotential subserosal mesenchymal . state of differentiation and ultimate fate of resident adherent and free-floating serosal cells following injury to determine the exact roles they play in normal and abnormal mesothelial repair. such as fibrinolytic proteases or growth factors that stimulate mesothelial healing. whereas adhesion had increased in the animals receiving MSCs 4–6 h after surgery. omental mesothelial cells may display phenotypic characteristics that are different from mesothelial cell populations present in other locations. Our studies demonstrated incorporation of free-floating mesothelial cells obtained from peritoneal lavage and peritoneal wall into injured serosa (Foley-Comer et al. with 3 × 108 of their own mesothelial cells.) injection of cultured autologous omental mesothelial cells in rabbits with staphylococcal-induced peritonitis significantly reduced the formation of adhesions. it is not clear whether the free-floating injected cells are different from the resident mesothelial cells of the serosal lining. Cell tracking studies were not performed in this study so the fate of the injected cells remains unknown. suggesting that omental mesothelial cells alone may not be the only cells involved in mesothelial regeneration. They isolated and cultured mesenchymal stem cells (MSCs) from skeletal muscle of neonatal rats and assessed their effect on the formation of peritoneal adhesions. Cells were injected i. 6.628 S.E. It is crucial that future studies elucidate the origin. Dead MSCs and smooth muscle cells had no effect on adhesion formation compared with saline controls. Bertram et al. injury to the internal organs and vessels. injection of cultured autologous rat omental mesothelial cells immediately after abrasion of the peritoneum reduced the number of adhesions compared to the control group. previously cultured and frozen. Vanni. The concept that these free-floating mesothelial progenitor cells may have stem cell-like qualities is supported by the findings of Lucas. Warejcka. (1999) also found that i. these approaches have shown limited success. impaired wound healing and difficulty of application.p. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 agents and barrier devices such as membranes and gels.

Tracy.. submesothelial cells lost vimentin immunoreactivity and progressively acquired high and low molecular weight cytokeratins. 1985. Yen et al. 1993. Taguchi. At a later stage.. irradiation and kinetic studies have also questioned the role of subserosal cells for mesothelial regeneration (Whitaker & Papadimitriou. For example. Bolen et al. In another study. new evidence suggests that the mesothelial cells themselves may be multipotential and have the ability to differentiate into various different cell types.. ultrastructural and immunohistochemical techniques to examine intermediate filament expression in reactive and non-reactive human serosal tissue. However. 1962. 1996. 7. begin to differentiate into mesothelial cells while migrating to the injured surface. 1987) provided the best support for a multipotential subserosal cell using light. 3). it has long been known that these cells can change to a fibroblastic phenotype with repeated passage.E. 1993). However. These cells expressed microvilli. suggesting FGF plays a key role in the phenotypic conversion of fibroblasts into regenerated mesothelial cells. The group demonstrated that normal surface mesothelial cells express low and high molecular weight cytokeratins whereas submesothelial cells express only vimentin. which when appropriately stimulated. Epithelial-mesenchymal transition of mesothelial cells Classically. It was suggested that these cells were differentiating towards a mesothelial cell phenotype and were responsible for the re-establishment of surface mesothelium. & Craighead. 1990) and from experimental animal models (Johnson & Whitting. Mutsaers et al. Hammar. formed adherens junctions and were immunoreactive for cytokeratin. demonstrated differentiation of surface cells into that consistent with mesothelial cells. was detected in the subserosal layer in the absence of mitotic activity in the original smooth muscle layer (Pampinella et al. Many groups have described the presence of cells with epithelial-like characteristics in the subserosal layer of biopsies from various pathological conditions (Bolen et al. This form of injury induced thickening of the subserosal layer with smooth muscle hypertrophy. 1990). This change in phenotype was inhibited following incubation of spheroids with anti-fibroblast growth factor receptor antibody.S. the authors concluded that resident keratin expressing subserosal mesenchymal cells transformed into myofibroblasts and subsequently into fetal-type smooth muscle cells a well as regenerating mesothelial cells (Buoro et al.. isolated mesothelial cells from normal serosal tissue or fluid demonstrate cobblestone epithelioid morphology in culture. and Naoe (2002) reported that cultured spheroids composed of free-floating multicellular clusters of rat pleural fibroblasts. and a transient expression of cytokeratin 18 in subserosal mesenchymal cells. Davila & Crouch. reducing cytokeratin and increasing vimentin expression (Mackay.. (1986. 1993. 1987. new muscle expressing smooth muscle myosin and desmin. In agreement with their previous findings (Buoro et al. Various growth factors can also induce mesothelial cells to change phenotype and express many of the characteristics associated with fibroblasts such as increased motility and enhanced ECM production (Fig. & McNutt. Bolen. Further support for a multipotential submesothelial cell comes from experimental findings following short-term bladder obstruction in a rabbit model. Whitaker et al.. a concept originally suggested by Klemperer and Rabin (1931). Taken together these findings would seem to support the view that a multipotential subserosal mesenchymal cell exists which can differentiate into myofibroblasts and possibly smooth muscle cells as well as mesothelial cells... Pampinella et al. Herrick. Indeed Raftery (1973) described the involvement of a subserosal precursor cell in the repair of the mesothelium. Buoro et al. S. that ‘appeared intermediate in form between primitive mesenchymal cells on one hand and proliferating fibroblasts or endothelial cells on the other’. 1996). (1992) in a similar study were unable to reproduce these findings and suggested that the staining pattern seen by Bolen and colleagues may be a result of mature mesothelial cells migrating into the subserosal connective tissue. 1986. However. These findings have customarily been explained by the theory that there exists a population of subserosal multipotential cells with the ability to differentiate along both mesenchymal and mesothelial pathways. EGF induces the reversible change to a fibroblastic phenotype that is accompanied by an increased expression . Indeed. 1996). However. Pampinella et al. 2000). Dobbie.. Iwahara. 1996). Shibuya. in biopsies from injured serosa. Amari. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 629 cells.E. 1993.

Peritoneal mesothelial cells isolated from dialysis fluid effluents displayed a mesenchymal phenotype that appeared to be related to both the duration of CAPD and to whether peritonitis had occurred. 2000. of ␤1 integrins. in particular ␣2␤1. & Kim. intermediate and gap junctions and active deposition of ECM. The second study by Yánez-Mo et al. 1994. a pattern which is stable throughout early passages (Gulyas. 1999). are proposed to be associated with progression through the differentiation process (Dobra et al. Various benign disorders. The expression of Wilms tumor susceptibility gene (WT1) and certain proteoglycans. & Faull.630 S. This seems an unusual concept because in contrast to mesenchymal stromal cells. and Lin (2003) demonstrated that transforming growth factor-␤1 (TGF-␤1) induced human omental mesothelial cells to transdifferentiate into myofibroblasts in vitro with the characteristic appearance of prominent RER. at different passage numbers of the same cell preparation. syndecan-4 and glypican. cell adhesion. Micrographs courtesy of Jason Tee. apart from during wound healing or tumour progression (Hay. the mechanisms involved in this process are not clear. Whitaker et al. produce effusions that often contain increased numbers of mesothelial cells thought to be derived from the reactive serosa. Furthermore. inflammatory factors and other mediators direct cells down various phenotypic pathways. Stanley. Mesothelial cells lost their epithelial morphology and . Indeed. 1999. and it is likely that in disease. ECM production. Chen. It has been suggested that these two different cell morphologies represent mesothelial cells at different stages of differentiation. stress responses and many other essential metabolic processes as the mesothelial cells underwent transformation. Owens & Milligan. Gulyas & Hjerpe. The authors proposed that the differentiated epithelial cells of the mesothelium convert into myofibroblasts and that the pathological features observed following CAPD may be due to the recruitment of fibrogenic cells from the mesothelium during serosal inflammation and wound healing. 3. 2003) with WT1 often being described as a mesothelial lineage marker. 1999). Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 Fig.E. cell proliferation. epithelial-like cells infrequently convert into fibroblasts in mature tissue. including liver cirrhosis. Herrick. 1999). (1986). they suggested that this could account for the intermediate filament staining pattern observed by Bolen et al. However.E. 1983. facilitating an enhanced adhesion to and migration on collagen type I (Leavesley. Yang. Gene expression analysis revealed a complex modulation of gene expression involving cytoskeletal organisation. these cells demonstrate both fibroblastic and epithelioid morphologies. Yang. innate immunity. Primary cultures of human pericardial mesothelial cells representing (A) epithelioid and (B) fibroblastic phenotypes. & Hjerpe. 1995). In culture. Dobra. Lee. EGF. Park. two recent reports investigating the pathological effects of continuous ambulatory peritoneal dialysis (CAPD) have provided strong evidence to support this concept. (1992) first suggested that mature mesothelial cells could transform into fibroblast-like cells in vivo and invade the underlying subserosal connective tissue. conspicuous smooth muscle actin myofilaments. PDGF and IL-1 beta have also been shown to stimulate increased collagen production in mesothelial cells (Harvey & Amlot. endometriosis or serosal inflammation. In the first study. Kim.. S. CAPD is known to cause peritoneal fibrosis leading to a failure of ultrafiltration however. (2003) also demonstrated that human mesothelial cells undergo a conversion from an epithelial to mesenchymal phenotype which occurred in patients following serosal injury.

Vascular grafts Despite considerable clinical research. invasive and fibrogenic features (Hay. 8. it is unclear whether the mesothelial cells that undergo trandifferentiation are a resident population in the mesothelial layer. Pittilo. for over a century these cells have been used to repair damaged tissues and organs. ICAM-1 and cytokeratins. failure frequently occurs because the luminal surface is thrombogenic resulting in thrombus formation and re-occlusion following implantation. it is currently unknown whether the mesothelial cells remain as myofibroblasts. 1985). 1973. Verhagen et al.S.. suggesting that these cells were derived from a local conversion of mesothelial cells. 1986). Clarke.. 1988. 2002. continue to differentiate into smooth muscle cells or revert back to surface mesothelial cells. and Woolf (1984) proposed that autologous mesothelial cells may represent a practical alternative to endothelial cells in vascular grafts. Campbell & Ryan. assessment of peritoneal biopsy specimens from patients undergoing CAPD showed the presence of mesothelial markers. 1998. inhibited platelet aggregation and released more prostacyclin than unseeded grafts in canine abdominal aorta replacements. 1984). the amorphous components of elastic fibres and basement membrane-like structures restricted to the basal region of the cell layer (Rennard et al. When acellular artificial prostheses are used in the reconstruction of small diameter vessels. Furthermore. S.. It has long been recognised that foreign objects introduced into the peritoneal cavity of the rat. the cells transform into fibroblast-like cells with pseudopodial protrusions and increased migratory. later studies using digested omental extract seeded onto knitted Dacron scaffolds and implanted 8. appeared to be involved in this process. Bearn et al. in addition to the known fibrinolytic and antithrombotic properties of mesothelial cells (Louagie et al. Bolen et al.. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 631 showed a decrease in the expression of cytokeratins and E-cadherin through induction of the transcriptional repressor snail. initiate an inflammatory response with the resultant granulation tissue covered by a layer of mesothelium (Ryan et al.. With time. the earlier concept of a multipotential subserosal cell being able to convert to both epithelial mesothelial cells and myofibroblasts (Raftery. Later ultrastructural studies showed that mesothelial cells deposited and organised ECM. Eskeland and Kjaerheim (1966) were first to demonstrate that a mesothelial membrane could be grown on the outer surface of a free-floating diffusion chamber placed in the peritoneal cavity of rats. Campbell. 1983. displayed anti-thrombogenic activity. Nevertheless. 1996). Based on these observations. (1988) showed that Dacron arterial grafts seeded with autologous mesothelial cells promoted luminal cell cover. 1973. . Bull et al.1. In addition. Mosse. irradiation. Studies by Bull et al. on fibroblast-like cells embedded in the subserosal layer. Tissue engineering potential of mesothelial cells Although there is a lack of information regarding the differentiation potential of mesothelial cells.. CAPD.’ a complex and generally reversible process that starts with the disruption of intercellular junctions and loss of apical-basolateral polarity typical of epithelial cells. mainly derived from the omentum. as endothelial replacements (Sparks et al. 2001). However. 1995). & Ryan. as well as being employed in a number of new tissue engineering applications. Major profibrotic and inflammatory cytokines. 1992. Subsequently. Herrick. including thick collagen fibres. rabbit or mouse. such as TGF-␤1 and IL-1B.E. many groups have investigated the efficacy of using mesothelial cells. The authors described this phenotypic conversion as ‘transdifferentiation.E. for example.. Cell seeding should decrease thrombogenicity of implanted vascular grafts but this application is hampered by the limited availability of autologous vascular endothelial cells.. originate from a serosal fluid subpopulation or are from a circulating blood-derived source. They also acquired a migratory phenotype with up-regulation of ␣2 integrins. malignancy or surgery. it raises the interesting possibility that mesothelial transdifferentiation may be wholly or partly responsible for the pathological changes that occur in the serosal layer following trauma caused by. no biological or synthetic grafts have been developed as an ideal substitute for small diameter arteries (Nerem & Seliktar. However. Theuer et al. and so alternative cell types have been sought. Furthermore. Machin. 1986) should be questioned. the authors do suggest that in light of these recent findings..

Cebotari. innervation of the tubes following transplantation into the rat anterior eye chamber appeared to have little effect on the differentiation of cells towards a smooth muscle cell phenotype.. S. Following end-to-end anastomosis with the aorta. The authors state that these grafts have several advantages over others in that they are biocompatible with the host tissue. Walles. Salacinski. Free-floating silastic tubing was implanted into the peritoneal cavity of rats and rabbits and after two weeks. although recent interest has stemmed from its multiple uses in reconstructive surgery (Liebermann-Meffert. fibronectin coated small diameter polytetrafluoroethylene (PTFE) scaffolds seeded with cultured omental mesothelial cells showed poor patency and increased neointimal thickening compared with non-seeded grafts following implantation into the carotid artery of the same dog (Verhagen et al. 2000). Punshon.E. Efendy.. & Seifalian. for example. Sorrentino. how similar the inner surface lining of mesothelial cells are to true endothelial cells. Other studies in which the infrarenal inferior vena cava was replaced with interposition grafts of either a peritoneal tube. The grafts remained patent. Herrick. many questions remain unanswered such as. 1994. When the tubes were everted and histologically assessed they consisted of an intima of non-thrombotic mesothelial cells. is this through a transdifferentiation process as described previously? Many authors remain to be convinced of the use of the peritoneal cavity as a feasible environment for growing functional bioartificial vascular grafts as reviewed by Moldovan and Havemann (2002). they also showed extensive denaturation of collagen and graft degeneration. In contrast. Campbell.. active stretch and neuronal imput on the differentiation of the cells within the mesothelial tubes was investigated in a subsequent study. However. showed reasonable tensile strength and were responsive to contractile agonists for at least 4 months. The omentum is essentially composed of two mesothelial sheets which enclose predominately adipocytes embedded in a highly vascularised connective tissue. The greater part of the omentum is associated with the stomach. Hamilton. & Campbell. Moreover. Krijgsman. The role of haemodynamic stress. although they found repopulation of the implanted grafts in the given time period. 1992).E. have produced more favourable results. and Mertsching (2002) repeated the work of Campbell et al.. suggested that the mesothelial cells were not retained on the graft 24 h later (Bearn et al. the use of mesothelial cells as endothelial cell replacements still remains a possibility and may prove important in.632 S. Until then. small intestines and transverse colon and forms an ‘apron-like’ structure covering abdominal . they have demonstrated patency for at least 4 months with 10–20% contractile responses compared with the control artery after transplantation.. a media of smooth muscle-like cells or myofibroblasts embedded in a collagen and elastic matrix. 1996). 2000). 1987. and are mesothelial cells in the ‘intimal’ layer subsequently replaced by local ingrowth of endothelial cells following transplantation to high pressure arterial sites. if the free-floating mesothelial cells of the peritoneal cavity are able to provide all the cell types found in the transplanted graft. Haverich. demonstrated that peritoneal lined grafts maintained a continuous circumferential cellular lining but showed no improvement in short term patency compared to PTFE alone (Theuer et al. which was also observed by cyclically stretching the tubes in vitro (Efendy. and Campbell (1999) using an alternative seeding method. Despite these disappointing findings.2. have a nonthrombogenic surface and develop elastic lamellae. 2003) is a better method for generating tissue engineered grafts. awaits further investigation. Omental grafts The scientific community has neglected the omentum for many years. Indeed. need no artificial mesh as part of the wall. 1998). Pasic et al. Furthermore. Whether prior seeding vascular scaffolds with mesothelial cells isolated from the omentum (Pearce et al. Campbell. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 as bilateral femoral artery replacements. the ones that remained free-floating were removed and processed. (1999) using decellularised allogenic scaffolds and. 8. there was a progressive increase in myofilament expression (evidence of smooth muscle phenotype) in the grafts over time. 2001) or peritoneal fluid (Tiwari et al. and an outer collagenous adventitia.. PTFE or PTFE lined peritoneum. the development of autologous coronary artery bypass grafts or arteriovenous access fistulae for hemodialysis patients.

The exact mechanism of this early revascularisation is unknown. 1975). & Duckett. which are present in high levels and can be isolated from the omentum. & Catsimpoolas. & Sitter. Mandl-Weber. In another study. Lundborg. 1993) and VEGF (Zhang et al. 1997. Cohen.. & Schuler. (1982) investigated the regeneration of a transected sciatic nerve through either preformed mesothelial chambers or autologous nerve grafts bridging a 10 mm gap. (1998) used free omental grafts to treat severe necrotising fasciitis and observed that necrotic tissue became revascularised resulting in acceptance of the graft and healing of the defect. Goldsmith. kidney. In a post-mortem study. The omentum is particularly susceptible to forming adhesions as it floats passively within the peritoneal cavity but rapidly adheres to inflamed or damaged tissues. the regenerating nerve was surrounded by a loose cellular stroma and a small amount of interstitial fluid. and axons from the left sciatic nerve reinnervated muscles in the right limb via the right sciatic nerve. Within the mesothelial chambers. Initial studies in a rat model by Lundborg et al. Castaneda and Kinne (2002) performed siatic nerve transections in rats and found that 25–30 mm defects bridged by an omental graft were fully healed with increased functional recovery and less scarring than end to end repair. Nerve grafts Regeneration of severed peripheral nerves is often incomplete due to loss or misdirection of nerve fibres and neuroma formation. are involved.. Griffith.E. 2002). Furthermore. nerve regrowth occurred when a preformed mesothelial tube bridged the gap between left and right sciatic nerves that had been transferred to the backs of rats (Danielsen. the conduction velocities across the gaps were similar. & Catsimpoolas. Chamorro et al. through either the release of growth factors or themselves being incorporated into the repairing tissue. thus increasing the efficiency of nerve regeneration. Chen. it has been suggested that various growth factors such as FGF (Chamorro et al. In the mesothelial chambers. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 633 organs. Additional studies demonstrated that when rabbit hypoglossal nerves were repaired using mesothelial chambers.E. 1990). its use as a pedicle graft tissue for clinical conditions involving revascularisation of ischaemic parts of the brain. It is worth noting that the fate and role of the mesothelial cells was not determined in any of these studies and therefore it is not clear whether they were in part responsible for the success of these grafts. 2001). Dahlin. Lee. heart and spinal cord (Goldsmith. 1993) properties. 1983). 8. 1997). Kretzler. Free omental grafts have been used in the treatment of numerous human disorders including neurodegenerative diseases such as Alzheimer’s disease.3. Kupferman. 1986. Early revascularisation and directional growth of sprouting axons was encouraged. (1993). Weibel and Manjo (1973) found that the omentum was the organ most frequently involved in adhesion formation and many workers have suggested that omental adhesions offer protection against more severe complications such as peritonitis and ischaemic bowel disease (Williams & White. hence. 1986). Duckett. Haslinger. Similar to the studies of Chamorro et al. It was suggested that grafts incorporating mesothelial .S. Piano et al. an organised multifascicular nerve trunk formed between proximal and distal stumps. & Chen. Herrick. the thin mesothelial lining found around the tube lacked primary inflammatory signs at follow-up after 1 year and showed no signs of compression (Dahlin & Lundborg. & Frizell. Remarkably. a significantly faster migration of radio-labelled proteins in the distal nerve segment was observed compared to sutured nerves (Danielsen. 1973. a well developed nerve structure was generated in the chamber between the nerve ends. Schlechter. Hasgood. which was found to contain trophic activity for cultured rodent sensory neurons. When the gap was 10 mm or less. In a subsequent study. 1984. however. Baraniewski. S. After 3 months there was no difference with respect to axonal density or distribution of axons between the two grafts. 1986) and neurotrophic (Chamorro et al. chronic leg ulcers and gastric ulcers (Weinzweig. The use of nerve replacements composed of artificial tubes seeded with isolated mesothelial cells as an alternative to primary nerve suture has been introduced as a biological approach to nerve injuries. Griffith. Goldsmith.. Part of the omentum’s ability to ‘rescue’ injured tissue is likely to be due to its angiogenic (Goldsmith. & Lundborg. spleen. (1993) used free omental grafts to facilitate nerve graft regeneration in rats by surrounding the nerve graft with omentum.

Wada. Thus. Danon. Does a mesothelial ‘stem’ cell exist? The biology of adult stem cells remains remarkably poorly understood and in general. This finding raised the interesting question of whether the coelomic mesothelium retains its ability to transform into multipotent mesenchymal cells in the adult. it would be desirable to imitate the environment of the inflamed diaphragmatic peritoneum in .E. 1999). the common progenitor of the endothelial and hematopoietic cell lineages. The authors suggest that a cell line derived from rat epicardial mesothelial cells acts in a similar manner to the bipotential vascular progenitor cells. during the healing phase of a chemical-induced peritonitis. 2001). tissue culture and animal experimental studies have convincingly demonstrated that adult mesothelial cells are capable of transdifferentiating from an epithelial to mesenchymal phenotype and this seems to depend on the presence of certain growth factors or cytokines (Yang et al. (1999) recently hypothesised that hemangioblasts. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 cells may have an advantage as they allow sliding of the repair site against surrounding tissues due to the secretion of surfactants (Dahlin & Lundborg. muscle. a stem cell population originally described by Yamashita et al. Indeed. originated from embryonic splanchic mesothelium. Indeed. Donna and Betta (1986) proposed that ‘the mesothelial cell was not only totipotent but represented real mesoderm that retained the potential to differentiate along embryonic developmental lines including to cartilage and bone’. Since then. The ability to produce cells that can progress down a variety of distinct cell lineages. Boland & Tuli. For example. For instance. A rich reservoir of adult stem cells resides in specific niches within the bone marrow microenvironment as well as in a variety of connective tissues. Based on this assumption. growing evidence based on its primitive embryological origin and ability to transdifferentiate strongly supports the idea that a population of mesothelial progenitor cells exist. when appropriately induced. as the authors state. The location and orientation of the fibres suggested an origin from mesothelial or submesothelial cells in granulation tissue rather than intrinsic diaphragmatic muscle satellite cells (Levine & Saltzman. it will be important to determine if the diaphragmatic mesothelium is different from mesothelium in other locations. where they are maintained in an undifferentiated and quiescent state. is one of the main characteristics of stem cells. Yanez-Mo et al. However. and that the differentiation of endothelial and blood cells was therefore from a common mesothelial-derived progenitor. (2000). bone. findings from several experimental models suggest that these cells may also form skeletal muscle and cartilage. 1994. fate or function of the mesothelial cells was not described in these studies. As well as the intriguing possibility that adult mesothelial progenitor cells are able to produce endothelium and smooth muscle. & Levine. as previously described. Reese. 2003. skeletal muscle fibres were found to develop de novo in the peritoneal lining of the adult rat diaphragm.. explants of adult rat epicardial mesothelium retain the ability to produce mesenchyme including smooth muscle cells in response to specific growth factors. 9. Munoz-Chapuli et al.. Herrick. S. even as clonally isolated cells. Perez-Pomares and Munoz-Chapuli (2002) showed that during development. Although a mesothelial stem cell has not been identified. epicardial mesothelium differentiates into endothelium or smooth muscle through an epithelial-mesenchymal transition (EMT) process. conclusive evidence demonstrating that adult human mesothelial cells are capable of differentiating along specific mesenchymal cell lineages is still lacking. cartilage and fat (reviewed by Tuan. artificial tubes lined by mesothelial cells appear to be important alternatives to conventional repair techniques for primary nerve repair and reconstruction of segmental defects. A later study provided evidence to support this theory. they suggested the term ‘mesoderma’ instead of mesothelioma to recognise the mesodermal origin of associated mesothelial tumours. If the mesothelium is the source of new skeletal muscle fibres. Although the origin. Using cell-labelling techniques and quail-chick chimeras. more extensive studies are required to confirm these findings. Osler. 2003). there is a lack of a unifying definition as well as specific markers to define them. Drakontides. mesenchymal stem cells (MSCs) have the potential to differentiate along specific mesenchymal lineages (multipotency) and form tissues that include endothelium. However. and Bader (2003) recently showed that in culture. 2003).634 S.E.

2003). Wilson. As well as an ability to differentiate along specific lineages upon stimulation. levels of cytokines and growth factors. Herrick. in experimental models. Growth factors levels. little is know regarding aspects of ageing or senescence of mesothelial cells. & Mohr. Depending on the local environment these progenitor cells may be able to progress down various differentiation pathways. 1987. Han. & Campbell. Bordi. & Mollo. bone and cartilage were found in peritoneal malignant mesotheliomas that were induced by i. 1986. 1997. in the human peritoneum. 1992). & Diethelm.S. The source of the cells that undergo this differentiation process remains controversial but the traditional view is that they are derived from a population of subserosal multipotential cells as described earlier. Although rare. S. Muhle. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 635 other areas of skeletal muscle damage where regeneration is needed. Surprisingly. 2000). Bifulco. However. any changes in. smooth muscle cells and endothelial cells. Girjes. & Rosai.p. Katz. Ernst. it is of no surprise that biopsies taken from human malignant mesothelioma express markers of osseous and cartilaginous differentiation (Donna & Betta. & Berroya. & Shostak. These progenitor cells may be resident in the mesothelial layer. for example. cell density and physical and mechanical stimuli may all contribute to the end product of differentiation. free-floating in the serosal fluid or alternatively. they may detach from the basement membrane and become free-floating progenitor cells in the serosal fluid before repopulating serosal lesions. other key features of stem cells are to remain in a quiescent undifferentiated state until provided with the signal to divide asymmetrically and undergo many more replicative cycles than normal. Bernardi. In addition. Montague. 1999.E.. Mazzucco. Denton. Flesher. may also affect ultimate progenitor cell fate (Fig.. injection of asbestos fibres (Rittinghausen. these cells may transdifferentiate into subserosal progenitor cells with the capacity to further differentiate into myofibroblasts.E. Kiyozuka et al. the mesothelial layer and free-floating cells are in continuous communication with peritoneal fluid and so Fig. Andrion. 1989). except that in culture they senesce 2. several other well-documented cases of mesenteric heterotopic ossification (or osseous metaplasia) and/or cartilaginous differentiation have been reported (Lemeshev. 1999. in light of recent findings. Yousem & Hochholzer. 4. and pH. 1983. Indeed. Fadare. identified through bone marrow transplant and Ly5 antigen expression. Future studies have yet to determine if these are characteristics of mesothelial progenitor cells. Salcuni. 1992). 4). Gotloib. whether serosal fluid contains survival factors that allow mesothelial progenitors to remain viable and proliferative or if it contains chemoattractants that cause circulating progenitor cells to home to . Lahr. This matter is further complicated by the observation that cells of a haemopoietic origin. it is also possible that a population of mesothelial cells may have the ability to form cells of different mesenchymal lineages. Kent. In addition. may be derived from a circulating multipotential cell population which enters serosal cavities via the vasculature. oxygen. Efendy. Hypothetical representation of a mesothelial progenitor cell residing in the serosal monolayer. Yannopoulos. Wajsbrot. Furthermore. At present. Furthermore. cell–cell interactions. Geller. however. Carter and Parkash (2002) found evidence of cartilaginous differentiation in human peritoneal tissue biopsies which did not appear to be associated with an intra-abdominal malignancy.5-fold faster than fibroblasts and in vivo senesce following exposure to dialysis fluids (Thomas et al. are able to differentiate into myofibroblasts and smooth muscle cells in response to a foreign body implanted into the peritoneal cavity (Campbell. Following injury. proteases.

vimentin (LaRocca & Rheinwald. Proliferation of rat pleural mesothelial cells in response to hepatocyte and keratinocyte growth factors. N. whether traditional mesothelial cell culture conditions select particular subsets of cells and stimulate them to progress down a certain differentiation pathway needs to be considered. 1997). to fully appreciate the potential of mesothelial progenitor cells. blood supply. & Abati. However. In addition. & Staub. differentiate and characterise mesothelial cells (Simsir et al. 23(3).. & Lager.. 1990. F. Davies. (1982). both pre. Albertine. Faris et al.. Applied Immunohistochemistry & Molecular Morphology. 1984).. immediate studies should focus on isolating reservoirs of mesothelial progenitor cells harboured in the three serosal cavities. 1999. 10. 1998. We acknowledge research funding from the Medical Research Council. UK (SEH) and Heart Foundation and Raine Medical Research Foundation. B.. Mesothelial cells still remain a viable alternative to endothelial cells in tissue engineered small diameter vascular grafts and as a inner lining for nerve replacements. 178–182. Y. M. there is only limited empirical information on how to select. Grenham Ireland and Dr. Coles. I. In vivo or ex vivo genetic manipulation of mesothelial cells has already been investigated for the delivery of therapeutic proteins to protect the peritoneal membranes of peritoneal dialysis patients (Hoff et al. propagate. American Journal of Respiratory Cell and Molecular Biology. For example. M. Al-Khafaji. it is essential that future studies are directed at elucidating their cellular and molecular characteristics to optimise identification. 2003). 1998). Afify. and lymphatic vessels of the . 1994. Herrick. desmin (Hurlimann. Roos. J. the limited findings presented to date are encouraging and suggest that an accessible and abundant supply of mesothelial progenitor cells is available for tissue repair. Even though this field is still in its infancy. HBME-1 (Donna et al. P. Exploitation of these progenitor cells may offer the opportunity to effectively repair a variety of tissues and expected long-term clinical applications are numerous. P. Simsir. References Adamson. Future directions To begin to address the question of whether a mesothelial stem cell exists.... although the point along a differentiation pathway (stem. In particular. & Cambria. Bakowska.636 S. K. A. M. Ross et al. J. either resident within various sites of the mesothelial lining or free-floating in serosal fluid. H. the cell markers that could be used are not well defined but those that are currently considered include cytokeratins 8 and 18. Cheville.. (2002). & Williams. Shepro. Nagy et al.. (2000). S. Diagnostic use of muscle markers in the cytologic evaluation of serous fluids. In addition. prior to implantation in the patient. Jenner. Paulino. R. Stylianou.. which may have applications for the treatment of inherited or acquired disorders requiring delivery of therapeutic proteins to the circulation. Mutsaers / The International Journal of Biochemistry & Cell Biology 36 (2004) 621–642 areas of serosal injury are all intriguing questions still to be answered. 1994). 10(2). or in situ in combination with appropriate biomaterials and mediators. 1996) and CD31 (Chung-Welch. calretinin (Fetsch. Patton. 2001) mesothelin (Chang & Pastan. Future studies that address this issue of identification are crucial. Structure. These therapeutic approaches may involve incorporating mesothelial progenitor cells induced to a particular differentiation state in either culture using specific growth factors. or genetic manipulation. isolation and expansion and to fully understand their differentiation capacity as well as the role they play in normal and abnormal repair events. the development of biocompatible peritoneal grafts to repair anastomosis and hernia defects is an interesting possibility. Acknowledgements We thank Dr. At present. regenerative medicine and tissue engineering applications. Denis Headon for useful comments. 2001). WT-1 (Muir.and post-injury. & Davila. J. 345–349.. & Prieditis. in the prevention of adhesions autologous mesothelial progenitor cells may be injected into the patient or immobilising factors administered that recruit the progenitor cells to the serosal cavity of the patient before surgery. Wiener-Kronish. H. A.E. Hekking et al. (1995) used this approach to demonstrate sustained systemic delivery of recombinant proteins. C.. progenitor or mature) at which the cells are isolated may alter the expression of some of these markers.E. 1997).. Furthermore. Australia (SEM).

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