Role of Müller cells in cone mosaic rearrangement and retinal remodelling in photoreceptor degenerations
Authors: García‐Ayuso Diego , Di Pierdomenico Johnny , Martínez‐Vacas Ana , Vidal‐Sanz Manuel , Villegas‐Pérez María Paz 
Published: December 2022

Photoreceptor degenerative diseases (e.g., retinitis pigmentosa or age‐related macular degeneration) are currently one of the leading causes of irreversible blindness in the world. Although their pathophysiological mechanisms may vary, they all share some features such as initial photoreceptor loss associated with glial activation and subsequent retinal remodelling. It is well known that glial activation is an early feature of photoreceptor degenerations that is involved in retinal remodelling, which, in turn, is thought to be the cause of the secondary death of the retinal ganglion cells. The mammalian retina contains three types of glial cells. Two types of macroglial cells: astrocytes and Müller cells, and microglial cells. Of them, Müller cells appear to be involved in the reorganization of the photoreceptor mosaic in empty rings of photoreceptor degeneration in the early stages of photoreceptor loss. Müller cells are the principal glial cells in the retina with a wide range of physiological and retinal structural support functions. The basic morphological scheme of Müller cells consists of a soma located in the inner nuclear layer from which an inner and an outer trunk emerge. The inner trunk contributes to the formation of the inner limiting membrane, and the outer trunk divides into complex rootlets spanning photoreceptor nuclei and finally forming the outer limiting membrane of the retina. In the early stages of photoreceptor degeneration, macroglial cell reactivity, namely increased expression of glial fibrillary acidic protein (GFAP) and Müller cells hypertrophy, leads to the formation of a glial scar or glial seal by hypertrophic Müller cell processes in the outer retina that may be related to the formation of empty rings of photoreceptor degeneration. Interestingly, Müller cells extend their external processes horizontally and radially within the rings of photoreceptor degeneration, filling the empty space left by dead photoreceptors. These rings become larger as photoreceptor loss increases, which suggests that they are the result of photoreceptor loss. As rings increase in size and, eventually, merge, the increased expression in the processes of Müller cells continues in the periphery of the rings. Perhaps in an attempt to complete the glial seal to isolate the remnant of the neural retina from the retinal pigment epithelium and choroid which, in turn, may represent a physical barrier to axonal regrowth and migration and therefore may impede the success of therapies aimed at replacing or substituting photoreceptors. Indeed, as photoreceptor loss progresses, the glial sea is more evident, covering large areas of the retina. Although the exact function of the glial seal is not known at this stage, it is thought that it may have a mechanical function in conferring some stability to the retina during the course of degeneration, but also a protective function, since in the later stages of retinal remodelling, focal gaps in the glial seal may allow the migration of retinal pigment epithelium cells to the inner retina, triggering a series of progressive events that eventually cause retinal ganglion cell death.