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Review
. 2022 Dec 30;11(12):1210-1218.
doi: 10.1093/stcltm/szac077.

Microglia: Friends or Foes in Glaucoma? A Developmental Perspective

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Review

Microglia: Friends or Foes in Glaucoma? A Developmental Perspective

Iqbal Ahmad et al. Stem Cells Transl Med. .

Abstract

Glaucoma is the most prevalent form of optic neuropathy where a progressive degeneration of retinal ganglion cells (RGCs) leads to irreversible loss of vision. The mechanism underlying glaucomatous degeneration remains poorly understood. However, evidence suggests that microglia, which regulate RGC numbers and synaptic integrity during development and provide homeostatic support in adults, may contribute to the disease process. Hence, microglia represent a valid cellular target for therapeutic approaches in glaucoma. Here, we provide an overview of the role of microglia in RGC development and degeneration in the backdrop of neurogenesis and neurodegeneration in the central nervous system and discuss how pathological recapitulation of microglia-mediated developmental mechanisms may help initiate or exacerbate glaucomatous degeneration.

Keywords: degeneration; glaucoma; microglia; neurogenesis; retinal ganglion cell.

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Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
(A) A schematic representation of microglia development with associated markers. The scheme is adapted from Li and Barres and include information from Butovsky et al. (B) A schematic representation of the adult eye and the laminar localization of microglia in the adult retina.
Figure 2.
Figure 2.
A schematic representation of 3 broad pathways for microglia influence on the onset and progression of glaucomatous degeneration. The dystrophic microglia represent those that are inherently abnormal due to mutations in genes expressed in microglia, exemplified by the TREM2 phenotype., C3 and C1q are complement proteins mediating complement-dependent synaptic toxicity via complement receptor, CR3.
Figure 3.
Figure 3.
A schematic representation of stem cell modeling of microglia-RGC interactions. Both microglia and RGCs are generated from iPSCs by directed differentiation in 2D culture. Glaucoma patient-specific and isogenic control RGCs are co-cultured with LPS-activated/control microglia together across a membrane to examine synaptic and cytokine toxicity of microglia, respectively. The co-culture paradigm is adapted in a microfluidic model of optic nerve regeneration (Teotia et al.) to examine the effects of microglia on axonal transport and regeneration. Each experimental paradigm is analyzed by population and single-cell RNA seq analysis for gene/drug discovery and subtype-based causes and effects, respectively.

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