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Editors Selection IGR 19-1

Basic Science: Neuroregeneration

Comment by Derek Welsbie on:

66837 Transplanted neurons integrate into adult retinas and respond to light, Venugopalan P; Wang Y; Nguyen T et al., Nature communications, 2016; 7: 10472

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Neuroregenerative strategies for glaucoma and other optic neuropathies will necessarily need to tackle the issue of retinal ganglion cell (RGC) replacement. Conventional thinking has been that exogenous, intravitreally-injected RGCs would have difficulty integrating into the retina, forming appropriate connections and regenerating axons that target the correct regions of the brain. In the February 2016 issue of Nature Communications, Venugopalan et al. used cross-species transplantation of primary RGCs to demonstrate that many of these challenges can be successfully overcome.

There are still significant challenges confronting RGC transplantation

Using a technique called immunopanning, primary RGCs can be isolated from mouse retina using antibodies against the RGC surface antigen, Thy1/CD90.¹ The Goldberg lab had previously labeled primary mouse RGCs and demonstrated that these donor cells could be visualized in the immune-privileged retina of a normal host rat, up to one week after intravitreal injection.² In the current work, the authors more thoroughly characterize the fate of these donor cells. Looking up to one month after injection, the authors found labeled RGCs integrated into the ganglion cell layer, the majority with evidence of neurite outgrowth and some with appropriately-stratified dendritic trees in the inner plexiform layer. Moreover, some cells expressed synaptic markers while others even displayed the canonical RGC ON-OFF electrophysiological response when stimulated with light. Finally, the authors found examples of donor RGCs with regenerated axons that found their way to the optic nerve head and back to visual structures in the brain.

While certainly promising, especially as groups are developing methods to produce a source of donor human RGCs using embryonic stem (ES) and induced pluripotent stem (iPS) cells,³ there are still significant challenges confronting RGC transplantation. First, only 10% of injections led to integration and even then, only 1-7% of cells survived, with far fewer actually managing to send axons back to the brain. Furthermore, while the mere presence of electrophysiological activity was exciting, the patterns were abnormal and immature-appearing. Future work will almost certainly focus on characterizing longer time points to see if further maturation occurs, augmenting the process by modulating cell death/axon regeneration pathways and establishing that transplantation is possible in diseased retinas.

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