Modeling axon growth and pathfinding of human retinal ganglion cells during development and disease

Albert Einstein College Of Medicine, Bronx NY

Investigators

Abstract

The application responds to the FOA PAR-23-046 to establish and utilize a microphysiological system for elucidating the mechanisms underlying early optic disc and stalk development, retinal ganglion cell (RGC) differentiation, axon growth, and pathfinding in human development and the pathogenesis of blinding retinal diseases. RGCs are retinal projection neurons that transmit light signals to the brain through the optic nerve. In glaucoma, RGC axons at the optic disc and RGC somas in the retina progressively degenerate, causing irreversible blindness. Regeneration of RGCs and their axons provides hope for restoring vision. To realize the hope, it is imperative to gain a deeper understanding of RGC differentiation and axon growth in humans. Human organoids are ground-breaking since they enable us to study cell differentiation directly in human-like tissues. We and others generate retinal organoids that display a stratified structure. In these retinal organoids, however, there is no proper RGC axon growth and pathfinding as the optic disc and stalk tissues that provide guidance cues for RGC axon growth and pathfinding are missing. Establishing human organoid models for RGC differentiation, axon growth, and pathfinding has a paradigm-shifting impact on studying human development and disease. We recently established telencephalon-eye organoids that comprised concentric zones of anterior ectodermal progenitors (CONCEPT), including the optic disc and stalk cells. Notably, these optic disc cells differentially expressed two retinal disease genes, whose mutations cause primary congenital glaucoma and hypoplasia of the optic nerve and optic chiasm, respectively. We hypothesize that coordinated specification of telencephalic and ocular tissues mediated by morphogens leads to the generation of the optic disc and stalk tissues that provide guidance cues for RGC axon growth and pathfinding. We will test the hypothesis in two Aims. Aim 1 is to dissect the mechanisms underlying the specification and differentiation of the optic disc and stalk tissues that provide guidance cues for RGC axon growth and pathfinding in CONCEPT organoids. Aim 2 is to determine RGC axon growth and pathfinding cues in humans using CONCEPT organoids and micro-patterned substrates. The accomplishments of this study will bridge major knowledge gaps in early optic disc and stalk development, RGC differentiation, axon growth, and pathfinding in human development and blinding retinal diseases. Organoid models and RGC isolation methods established here enable the development of RGC- protective drugs and RGC replacement therapies in treatments for glaucoma.