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Retinal Ganglion Cell Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration

The Retinal Ganglion Cell (RGC) Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) consortium will advance translational development of vision restoration therapies for glaucoma and other optic neuropathies by assembling an international group of >200 leading and emerging investigators from related fields.

Goals of the RReSTORe consortium are:

Why this initiative is important

Vision loss in optic neuropathies results from death of RGCs, the retinal projection neurons which transmit visual information from retinal neurons (bipolar cells) to retinothalamic brain targets via the optic nerves and optic tracts. Though some species of fish, birds, and amphibians possess ocular regenerative capabilities, human optic neuropathies cause permanent visual deficits because mammalian RGCs are not spontaneously repopulated. Therefore, vision loss is presently irreversible in patients suffering from a range of primary optic neuropathies including glaucoma, ischemic optic neuropathy, optic neuritis, and other inflammatory, toxic, metabolic, inherited, and traumatic optic nerve diseases.

How Can Vision be Restored in Optic Neuropathy?

RGC replacement poses a significant challenge because of the inherent complexity of this neuronal class. Prior work supports the premise that RGC replacement is feasible, as individual milestones in RGC replacement have been attained (Figure 1), including RGC differentiation from stem cells, retinal integration of transplanted RGCs, axonal extension through the optic nerve and into the brain, and RGC axon (re)myelination. However, collaborative efforts among interdisciplinary teams are required to brainstorm new ideas, develop rigorous approaches to execute them, and build teams to bring these ideas to fruition, in order to achieve complete RGC pathway replacement. The National Eye Institute (NIH) has prioritized retinal neuronal replacement as part of its strategic goals and is supporting this challenge through the Audacious Goals Initiative (AGI), which promotes collaborative approaches to retinal regeneration that are necessary given the complexity of this task.

RGC replacement milestones, which have been partly achieved in isolation. (1) Develop a reliable source of transplantable RGCs. (2) Deliver donor cells (red) safely. (3) Promote long-term donor RGC survival in the recipient eye. (4) Establish retinal localization and neuritogenesis. (5) Form synaptic connectivity with host retinal interneurons in the inner plexiform layer. (6) Conduct light-evoked, photoreceptor-transduced signals within the visual pathway. (7) Achieve axon growth toward the optic nerve head and into the optic nerve. (8) Develop myelination of new axons. (9) Reinnervate retinorecipient nuclei, including suprachiasmatic nucleus, lateral geniculate nucleus, olivary pretectal nucleus, and superior colliculus. Reprinted from: Zhang KY, Aguzzi EA, and Johnson TV. Retinal ganglion cell transplantation: Approaches for overcoming challenges to functional integration. 2021. Cells. 10(6):1426.

Subtopic Workgroups

RReSTORe aims to exist to complement other collaboratives efforts. RReSTORe will prioritize inclusion of scientists from diverse backgrounds, especially trainees and early career scientists, and adopt a structure that maximizes collaborative and sustained virtual and in-person discussions to foster interpersonal engagement and innovative approaches to RGC regeneration. Our discussions and our work will focus on five major topics: 

1) RGC Development and Differentiation: Stem Cell Biology and Neurogenesis; Transdifferentiation; Organoids and Assembloids; RGC subtype identification and specification

2) Transplantation Methods and Models: Transplantation Techniques; In Vivo Imaging and Functional Assays; Large Animal Models of Optic Neuropathy; Transplant Immunology

3) RGC Survival, Maturation, and Host Interactions: Neuroprotection, Neurovascular Coupling; Macroglial Interactions; Microglial Interactions

4) Inner Retinal Wiring: RGC Migration, Tiling, and Patterning; RGC dendritogenesis and Inner Plexiform Layer Sublaminar Targeting; Synaptogenesis in the Inner Plexiform Layer; Functional Integration Assays

5) Eye-to-Brain Connectivity: Pathfinding, Targeting, and Projection Specificity; Synaptogenesis in the Brain; Myelination; Implications of Anterograde Transsynaptic Degeneration


RGC Development and Differentiation

- Stem cell biology and neurogenesis
- Transdifferentiation
- Organoids and assembloids
- RGC subtype identification and specification

Transplantation Methods and Models

- Transplantation techniques
- In vivo imaging and functional assays
- Large animal models of optic neuropathy
- Transplant immunology

RGC Survival, Maturation, and Host Interactions

- Neuroprotection
- Neurovascular coupling
- Macroglial interactions
- Microglial interactions

Inner Retinal Wiring

- RGC migration, tiling, and patterning
- RGC dendritogenesis and inner plexiform layer sublaminar targeting
- Synaptogenesis in the inner plexiform layer
- Functional integration assays

Eye-to-Brain Connectivity

- Pathfinding, targeting, projection specificity
- Synaptogenesis in the brain
- Myelination
- Implications for anterograde transsynaptic degeneration

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