UC Davis

Mammalian vision begins in the retina, the layer of light sensitive neural tissue that lines the back of the eye, that is comprised of six main neuronal cell types: photoreceptors, bipolar cells, horizontal cells, amacrine, and retinal ganglion cells (RGCs). When light enters the eye and contacts the photoreceptors, a cascade of signals is sent through the highly organized structure of the retina until it reaches the RGCs, the output neurons of the retina. RGCs play a critical role by projecting the only axons that leave the retina, making the resulting nerve, called the optic nerve, the only connection between the eye and the brain. The optic nerve and the RGC population is the target of many retinal degenerative diseases, including glaucoma, which affects more than 70 million people worldwide. However, there are few treatments for glaucoma, and none can restore any vision loss. Therefore, development of alternative methods like retinal ganglion cell replacement therapy is an urgent need.In this dissertation, I investigate the barriers to successful RGC replacement, specifically the establishment of a reliable source of donor cells, the survival of donor cells, and the physical barriers within the host eye. Using two transgenic RGC reporter mice, the Isl2-GFP and Brn3b- mCherry lines, I found that MAP4K4 inhibition can increase the survival of RGCs during the in vitro production of RGCs, as well as post intravitreal transplantation. I also show that the ocular immune system actively targets donor RGCs and that intravitreal RGC transplantation causes transient retinal inflammation. Additionally, I show that mechanical disruption of the inner limiting membrane causes transient activation of immune cells to the disruption site. Lastly, this dissertation details the contributing factors to a successful RGC transplantation, including evidence of protein material transfer between donor and host RGCs. Together, I find that there is great promise to the development of RGC transplantation, but a complex system of barriers must be addressed before a reproducible method can be developed for clinical applications.