Chapter 5 - Restoring Vision to the Blind: Endogenous Regeneration

The human eye is made up of many tissues, each of which directly or indirectly influences our visual perception of the world. Tissues that directly impact vision include the cornea, lens, retina, and optic nerve. The cornea and lens serve to focus light as it enters into the eye; this light is detected and analyzed by the retina and the visual signal communicated to the rest of the brain via retinal ganglion cell (RGC) axons that form the optic nerve. Because they directly influence our vision, damage to any one of these tissues, due to disease or injury, can dramatically impact one’s quality of life. Many approaches are being developed to aid those who suffer from vision loss due to damage of these tissues; some of which have been quite successful, like corneal transplants, corneal epithelial regeneration, and artificial intraocular lenses. However, approaches to treat damage of the retina and optic nerve have proven more challenging. Unlike mammals, some vertebrate species are able to repair damage to the retina and optic nerve via endogenous regenerative events. Two fundamentally different categories of neuronal regeneration are important in the eye: neurogenesis (cell proliferation leading to replacement of neurons that have been lost) and axonal regeneration (regrowth of retinal ganglion cell axons following damage to the optic nerve). Depending on which cells are damaged, and the vertebrate species being studied, regeneration of retinal neurons through neurogenesis is accomplished by mitotic activation of retinal pigment epithelial (RPE) cells, retinal progenitor cells in the ciliary marginal zone (CMZ), or M€ uller glia. For optic nerve regeneration, RGCs whose axons are severed exhibit an axonal growth-permissive state. In both types of regeneration, immune cells and injury-related changes likely play a critical but poorly understood role. Importantly, these regenerative events ultimately can lead to the restoration of visually mediated behaviors. While mammals do not actively demonstrate these modes of regeneration in response to retinal disease or injury, current research supports the possibility that at least some of these regenerative cell types maintain an intrinsic regenerative potential in mammals and that this potential could be harnessed for retinal repair if the proper stimuli were provided. One can easily imagine how advantageous it would be to treat human retinal disease using endogenous reparative strategies. The purpose of this targeted session was to review the current state of research aimed at stimulating endogenous regeneration of retinal neurons and axons in the optic nerve and to provide guidance for future research. To this end, we provide a brief background describing the various modes of retinal and optic nerve regeneration employed by species that exhibit a robust regenerative response (amphibians and teleost fish) and those that demonstrate a limited regenerative response (birds). A discussion of progress made in initiating endogenous regenerative events in nonregenerative species (mammals) is then presented. Finally, recommendations are provided to stimulate and direct future research in this field.