neuroregeneration

# Introduction Glaucoma is a leading cause of irreversible blindness worldwide because the **retinal ganglion cells (RGCs)** that connect the eye to the brain die and cannot regenerate ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4356355/#:~:text=Glaucoma%2C%20the%20worldwide%20leading%20cause,an%20unlimited%20source%20of%20cells)). Without RGCs, visual signals from the retina cannot reach brain centers (like the lateral geniculate nucleus and superior colliculus), so vision is lost. Current glaucoma treatments (e.g. lowering intraocular pressure) can protect surviving RGCs but **cannot restore** those already lost ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7211134/#:~:text=Restoration%20of%20vision%20in%20patients,regeneration%20continue%20to%20be%20refined)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11642712/#:~:text=Glaucoma%20is%20a%20leading%20cause,the%20central%20nervous%20system%20is)). Stem-cell therapy aims to replace lost RGCs by differentiating human pluripotent stem cells (either embryonic stem cells, ESCs, or induced pluripotent stem cells, iPSCs) into RGCs and transplanting them into the eye ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4356355/#:~:text=Glaucoma%2C%20the%20worldwide%20leading%20cause,an%20unlimited%20source%20of%20cells)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7211134/#:~:text=Restoration%20of%20vision%20in%20patients,regeneration%20continue%20to%20be%20refined)). In principle this could supply an *unlimited source* of retinal neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4356355/#:~:text=difficulties%20in%20isolating%20and%20culturing,an%20unlimited%20source%20of%20cells)). But realizing this vision requires surmounting enormous challenges: the new RGCs must survive, grow axons through the eye’s exit (the lamina cribrosa) into the optic nerve, navigate long distances to precise brain targets, form functional synapses, and become myelinated – all in the inhibitory environment of the adult central nervous system. This article reviews the state of the art in deriving RGCs from human stem cells and transplanting them in animal models. We then discuss critical barriers to success – axon extension through the lamina cribrosa, guidance to thalamic and collicular targets, synapse formation, and myelination – as well as safety issues (immune rejection, tumor risk) and delivery methods (intravitreal vs. subretinal injection). Finally, we give a realistic outlook for when “first-in-human” trials in glaucoma might be feasible and what outcome measures they would require. Throughout, we strive for clarity: key terms are kept bold and any technical concepts are explained for a lay audience. ## Differentiating RGCs from Human Pluripotent Stem Cells Scientists have developed many protocols to turn human ESCs or iPSCs into RGC-like neurons. Typically, stem cells are first guided

Stem Cell–Derived RGC Transplantation: From Petri Dish to Optic Tract

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