**4. ECM implications in retinal pathologies**

One of the most specialized forms of ECM is the basement membrane, a flexible, tough, and thin sheet of very well-organized components of the ECM. The functions of basement mem‐ branes are to act as platforms for cell adhesion, to provide structural support to a tissue, to divide tissues into compartments, and to regulate cell behavior including polarity. Although small in volume and very thin (typically 40–120 nm), it has a critical role in the architecture of the body [103, 104]. Although the precise composition of the mature basal lamina varies from tissue to tissue and even from region to region in the same lamina, it typically contains the glycoproteins, laminin, type IV collagen and nidogen (also called entactin), along with perlacan [105]. Other common basal lamina components are fibronectin and type XVIII collagen. Interactions of cells with basement membranes are mediated by trans-membrane cell surface receptors, which connect the cytoskeleton of the cell with the extracellular environment, leading to the formation of focal adhesions [88, 106].

The mature polarized retina is structurally and functionally supported by two basement membranes that act as boundaries for the neural retina (**Figure 2**). The two basement mem‐ branes are (i) the Bruch's membrane, at the interface of the RPE and the choroid and (ii) the inner limiting membrane (ILM) at the interface of the neural retina formed by the endfeet of Müller cells and the vitreous body [107]. Changes in the organization or composition of these basement membranes lead to various pathologies including diabetic retinopathy, age-related macular degeneration, proliferative vitreoretinopathy or retinal detachment [108–111].

**Figure 2. Schematic drawing of the cellular components of the retina, glia neurons**. The different cell types are placed in the location of a standard large mammalian retina. Note the interactions between the cells and the blood ves‐ sels (BV). Amacrine cells (A), astrocytes in green (AS), bipolar cells (B), cones (C), ganglion cells (G), horizontal cells (H), Müller cells in blue (M), microglia in red (Mi), rods (R). Note the location of the different layers of the retina, from the most internal: optic nerve (ON), nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), in‐ ner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), outer segment layer (OS), pigment epithelium (PE), choroid (Ch). In green the two limiting membranes the Bruch's and the inner limiting membrane (ILM). In parallel to the drawing electron microscopy pictures of pig retinas showing both membranes.

The Brunch´s membrane is not only providing physical support for RPE, it also regulates RPE differentiation and acts as a barrier that prevents choroidal neovascularization, a process in which choroidal vascular cells inappropriately invade the retina [112, 113]. Alterations in the composition or organization of the Brunch´s membrane compromises the normal function of RPE cells and this disruption results in retinal pathologies including age-related macular degeneration [113].

The ILM lies on the vitreal side of the retina which is the opposite side of the retina from Bruch ´s membrane. The ILM constitutes the interface between the retina and the vitreous but is also responsible for organizing and maintaining the laminated structure of the retina and guiding astrocyte migration during vascular development [114]. Disruptions or changes in the ILM are associated with retinal dysplasia as well as retinal pathologies such as diabetic retinopathy, proliferative vitreo-retinopathy [114, 115].
