Review
Mesothelial progenitor cells and their potential in tissue engineering

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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.

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 et al., 1997, Mutsaers 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.

Section snippets

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 development, the intraembryonic mesoderm on each side of the neural groove

Functions of the mesothelial cell layer

As well as providing a slippery, non-adhesive epithelial surface, the mesothelial layer performs many diverse functions which are important in the maintenance of serosal homeostasis. These include transport and movement of fluid and particulate material across serosal cavities, regulation of leucocyte migration in response to inflammatory mediators, synthesis of pro-inflammatory cytokines, growth factors and ECM molecules, control of coagulation and fibrinolysis, and antigen presentation. These

Mesothelial healing

Hertzler (1919) was the first to observe that small and large peritoneal wounds healed in the same amount of time. 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. Since then, many studies involving a wide range of experimental model systems have been performed to elucidate the mechanisms regulating the regeneration process.

It is generally agreed that the healing process

Adhesion formation

Adhesions are a common consequence of serosal injury in all three serosal cavities leading to serious complications such as intestinal obstruction, chronic pain and infertility in women. 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, the origin of which was unclear (Herrick et al., 2000, Sulaiman et al., 2001).

It has been proposed that adhesions form

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 cells, which when appropriately stimulated, begin to differentiate into mesothelial cells while migrating to the injured surface. 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., 1986, Davila & Crouch, 1993; Bolen, Hammar, &

Epithelial-mesenchymal transition of mesothelial cells

Classically, isolated mesothelial cells from normal serosal tissue or fluid demonstrate cobblestone epithelioid morphology in culture. However, it has long been known that these cells can change to a fibroblastic phenotype with repeated passage, reducing cytokeratin and increasing vimentin expression (Mackay, Tracy, & Craighead, 1990). Various growth factors can also induce mesothelial cells to change phenotype and express many of the characteristics associated with fibroblasts such as

Tissue engineering potential of mesothelial cells

Although there is a lack of information regarding the differentiation potential of mesothelial cells, for over a century these cells have been used to repair damaged tissues and organs, as well as being employed in a number of new tissue engineering applications.

Does a mesothelial ‘stem’ cell exist?

The biology of adult stem cells remains remarkably poorly understood and in general, there is a lack of a unifying definition as well as specific markers to define them. 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, where they are maintained in an undifferentiated and quiescent state. The ability to produce cells that can progress down a variety of distinct cell lineages, even as clonally

Future directions

To begin to address the question of whether a mesothelial stem cell exists, immediate studies should focus on isolating reservoirs of mesothelial progenitor cells harboured in the three serosal cavities, either resident within various sites of the mesothelial lining or free-floating in serosal fluid, both pre- and post-injury. At present, there is only limited empirical information on how to select, propagate, differentiate and characterise mesothelial cells (Simsir et al., 1999; Stylianou,

Acknowledgements

We thank Dr. Grenham Ireland and Dr. Denis Headon for useful comments. We acknowledge research funding from the Medical Research Council, UK (SEH) and Heart Foundation and Raine Medical Research Foundation, Australia (SEM).

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