Idiopathic preretinal glia in aging and age-related macular degeneration

Abstract

During analysis of glia in wholemount aged human retinas, frequent projections onto the vitreal surface of the inner limiting membrane (ILM) were noted. The present study characterized these preretinal glial structures. The amount of glial cells on the vitreal side of the ILM was compared between eyes with age-related macular degeneration (AMD) and age-matched control eyes. Retinal wholemounts were stained for markers of retinal astrocytes and activated Müller cells (glial fibrillary acidic protein, GFAP), Müller cells (vimentin, glutamine synthetase) and microglia/hyalocytes (IBA-1). Retinal vessels were labeled with UEA lectin. Images were collected using a Zeiss 710 confocal microscope. Retinas were then cryopreserved. Laminin labeling of cryosections determined the location of glial structures in relation to the ILM. All retinas investigated herein had varied amounts of preretinal glial. These glial structures were classified into three groups based on size: sprouts, blooms, and membranes. The simplest of the glial structures observed were focal sprouts of singular GFAP-positive cells or processes on the vitreal surface of the ILM. The intermediate structures observed, glial blooms, were created by multiple cells/processes exiting from a single point and extending along the vitreoretinal surface. The most extensive structures, glial membranes, consisted of compact networks of cells and processes. Preretinal glia were observed in all areas of the retina but they were most prominent over large vessels. While all glial blooms and membranes contained vimentin and GFAP-positive cells, these proteins did not always co-localize. Many areas had no preretinal GFAP but had numerous vimentin only glial sprouts. In double labelled glial sprouts, vimentin staining extended beyond that of GFAP. Hyalocytes and microglia were detected along with glial sprouts, blooms, and membranes. They did not, however, concentrate in the retina below these structures. Cross sectional analysis identified small breaks in the ILM above large retinal vessels through which glial cells exited the retina. Preretinal glial structures of varied sizes are a common occurrence in aged retinas and, in most cases, are subclinical. While all retinal glia are found in blooms, vimentin labeling suggests that Müller cells form the leading edge. All retinas investigated from eyes with active choroidal neovascularization (CNV) had extensive glial membranes on the vitreal surface of the ILM. Although these structures may be benign, they may exert traction on the retina as they spread along the vitreoretinal interface. In cases with CNV, glial cells in the vitreous could bind intravitreally injected anti-vascular endothelial growth factor. These preretinal glial structures indicate the remodeling of both astrocytes and Müller cells in aged retinas, in particular those with advanced AMD.

Different Ipsi- and Contralateral Glial Responses to Anti-VEGF and Triamcinolone Intravitreal Injections in Rats

“…Astrocyte hypertrophy and Müller cell reaction have been previously reported in the retina of different animal species after IVI. 79,82,86,87 Overall, and in accordance with previous studies, our results suggest that macroglial cells are more sensitive to IVI than microglial cells and that the reaction is different depending on the injected substance.…”

“…Although we removed most of the preservative present in the commercial preparation of triamcinolone as previously described, 88 the substance or the remaining preservative may have cellular toxic effects, 88,89 and the retina may react to stress with the initiation of glial blooms or preretinal membranes as has been observed in degenerating retinas. 87,90,91 On the other hand, treatment with the anti-VEGF aflibercept and ranibizumab has been shown to activate neonatal rat Müller cells in culture, and it has been proposed that it may be responsible for the therapeutic effects of these drugs. 92 …”

Expression of peptidylarginine deiminase 4 in an alkali injury model of retinal gliosis

“…Gliosis in all areas of the central nervous system (CNS) has many similar characteristics [3],[4]. In the retina, gliosis occurs in Müller glial cells and ganglion cell layer astrocytes [2],[5]. These cells provide trophic and structural support to neuronal cells of the retina [1],[2].…”

Immunohistochemical Analysis of a Vitreous Membrane Removed from a Patient with Incontinentia Pigmenti-Related Retinal Detachment

“…According to them, epiretinal membranes originate from retinal pigment epithelial cells, fibrous astrocytes, fibroblasts, and macrophages [10]. Edwards et al [11] studied the preretinal membranes in age-related macular degeneration with antibodies to GFAP (marker of retinal astrocytes and activated Müller cells), vimentin, glutamine synthetase (markers of Müller cells), and ionized calcium binding adaptor molecule-1 (IBA-1; marker of microglia and hyalocytes). Both astrocytes and Müller cells were identified in the membranes.…”