Matrix and the retinal pigment epithelium in proliferative retinal disease

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Abstract

In their normal state, RPE cells are strongly adherent to Bruch's membrane. Certain pathological conditions such as retinal detachment cause an injury-type response (probably augmented or induced by the local accumulation of a variety of substances which modulate cell behaviour) in which RPE begin to dissociate from the membrane. This RPE-Bruch's membrane separation may be mediated by proteins with counter-adhesive properties and proteolytic enzymes, partly derived from the RPE themselves. Concomitant with the RPE disassociation, the cells begin to lose tertiary differentiation characteristics and gain macrophage-like features.

When the “free” RPE arrive at the surface of the neuroretina, they may attach to or create a provisional matrix. Some of the cells adopt a fibroblast-like phenotype. This phenotype is similar to that of the dermal fibroblast during cutaneous wound repair and the fibroblastic RPE synthesise the types of matrix components found in healing skin wounds. Many of these molecules in turn further modulate the activities of the cells via several families of cell surface receptors, while the RPE continue to remodel the new matrix with a range of proteolytic enzymes. The resulting tissue (or membrane) has many of the features of a contractile scar and is the hallmark of the condition known as proliferative vitreoretinopathy (PVR). Thus the development of PVR, and the resulting tractional distortion of the neuroretina, appears to be dependent on RPE-matrix interactions. The interactions present a number of potential therapeutic targets for the management of the disorder.

Introduction

Proliferative retinal diseases are characterised by the formation of scar-like fibrocellular membranes on the retinal surfaces. Membranes on the vitreous surface of the retina are called epiretinal membranes (Cibis, 1965) while those beneath the neuroretina are often known as subretinal membranes. Like many evolving scars, the membranes can contract. Membrane contraction impairs vision by distorting or detaching the sensory retina (see for example Roth and Foos, 1971; McLeod et al., 1981). Moreover, the membranes frequently are opaque and thus epiretinal membranes may impede light ingress to the retina.

The membranes may be divided into two main groups. One group arises as a consequence of retinal ischaemia, as in proliferative diabetic retinopathy. Typically, ischaemic retinopathy membranes are vascularised and do not contain many retinal pigment epithelial cells (RPE) unless there is a coexisting defect in the neuroretina (Hiscott et al., 1994). Conversely, the second group of membranes often are replete with RPE (reviewed by Machemer, 1978, Machemer, 1989) but tend to be avascular (reviewed by Hiscott and Grierson, 1994). Avascular, RPE-rich membranes most often arise following retinal hole formation, as in “rhegmatogenous” retinal detachment (RRD) and its treatment (Kampik et al., 1981; Michels, 1982). RRD occurs when a defect in the sensory retina permits fluid components of degenerate vitreous to gain access from the vitreous cavity to the potential space between the neuroretina and the RPE. The retinal detachment resolves after (surgical) closure of the retinal hole, but about 10% of detachments are complicated by epi- and/or sub-retinal membrane formation (which may redetach the retina). This condition has had a variety of names (Table 1) and the term Proliferative Vitreoretinopathy (or “PVR”) (The Retina Society Terminology Committee, 1983) has been generally accepted.

Although RPE have emerged as key players in PVR membranes, phenotypically the cells in the membranes are very different from the normal RPE on Bruch's membrane (Grierson et al., 1987, Grierson et al., 1994). Instead of forming a polarised monolayer, RPE displaced to PVR membranes look and behave like wound fibroblasts or macrophages. This RPE “dedifferentiation” or “transdifferentiation” to a wound repair phenotype is attended by profound changes in the surrounding extracellular matrix (Grierson et al., 1994). Since it is now apparent that matrix-cell interrelationships are important regulators of cell behaviour in a wide range of biological processes including wound repair (see below), such interactions may provide clues for the future management of PVR. Moreover, PVR may be regarded as a “model” in which to examine the relationship between matrix and cell differentiation or phenotype in general. This article explores some of the associations between PVR, RPE and their matrix.

Section snippets

Matrix and RPE in health: the RPE and Bruch's membrane

In the normal eye, the RPE forms a confluent monolayer with the apices of the RPE closely applied to the photoreceptor outer segments. The lateral aspects of the cells attach to their neighbours, while the basal surfaces of the RPE adher to Bruch's membrane. Traditionally, Bruch's membrane is regarded as a pentalaminar structure comprising the choriocapillaris basement membrane on the outer surface of the membrane, two collagenous zones divided by an elastic layer, and the RPE basement membrane

Matrix and RPE in disease: PVR membrane components

In the early stages of PVR development, adhesive interactions between some RPE cells and Bruch's membrane must be lost to permit the cells to start their journey to the surfaces of the neuroretina. RPE detaching from Bruch's membrane appear rounded or macrophage-like (Machemer and Laqua, 1975; Mandelcorn et al., 1975; Mueller-Jensen et al., 1975; Vidaurri-Leal et al., 1984; Machemer et al., 1978). The detached cells are probably swept through retinal holes as fluid vitreous is exchanged between

Collagens

It has long been recognised that “PVR-type” membranes contain a fibrous component (Parsons, 1905; Samuels, 1930; Klein, 1955) and thus it was not surprising that electron microscopic studies showed that PVR membranes possess collagen. Several collagen subtypes, including types I to V, may be present in epiretinal membranes (Scheiffarth et al., 1988, Scheiffarth et al., 1989; Jerdan et al., 1989, Morino et al., 1990) (Fig. 4). The presence in the membranes of collagen types not normally found in

Matrix as modulator of RPE behaviour: matrix receptor expression by RPE in PVR

It would be expected that RPE cells express receptors corresponding to important regulators of cell activities in the PVR membrane matrix. Several of the matrix components present in PVR membranes are known to exert at least some of their effects on cell behaviour by the integrin family of cell surface receptors (see above; Hynes, 1987, Hynes, 1992). These heterodimeric receptors mediate such key cellular activities as proliferation and migration by recognising various amino acid sequences (eg

Matrix remodelling by RPE: matrix proteases in PVR

The matrix is undergoing continuous change throughout wound healing and it is apparent that RPE can synthesise many matrix components during PVR development. Throughout PVR, it seems likely that a cocktail of growth factors derived from various sources such as periretinal and other ocular cells, immigrant macrophages and haematogenous components (following breakdown of the blood-retina barrier) induce or augment RPE activities such as matrix synthesis (reviewed by Hiscott and Grierson, 1994).

Matrix and RPE in vascularised proliferative retinal disease

Fibrovascular epiretinal membranes (eg in proliferative diabetic retinopathy) may contain RPE cells (Smith et al., 1976; Hamilton et al., 1982). Most of the RPE-containing membranes of proliferative diabetic retinopathy occur in eyes with a coexisting retinal hole (Hiscott et al., 1994). Although these membranes generally do not contain such a high proportion of RPE cells as PVR membranes, we have estimated that occasionally RPE may make up about a fifth of the cells (Hiscott et al., 1994). It

Conclusions and future directions

It is evident that, like the extracellular matrix of reparative phenomena elsewhere in the body, the matrix in proliferative retinopathy membranes is not merely a passive space filler. Indeed, the matrix almost certainly plays a crucial role in mediating the activities of the cells involved and hence in the development of the disease. The effect of the matrix on RPE activities is likely to be profound because many RPE in PVR membranes are enmeshed three-dimensionally in matrix instead of

Acknowledgements

Our research has been supported by the Guide Dogs For The Blind Association, North West Regional Health Authority R&D Directorate, the Wellcome Trust, the Royal College of Surgeons of Edinburgh and The Blind Asylum, Research into Eye Disease, the St. Paul's Foundation for the Prevention of Blindness and the Research and Development Fund of the University of Liverpool.

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