Improvement of donor human retinal ganglion cell survival through modulation of microglia

Abstract Stem cell-derived retinal ganglion cell transplantation therapy offers a promising avenue for restoring vision in patients with significant retinal ganglion cell (RGC) loss. The major challenge in this therapeutic approach is ensuring the survival of transplanted donor human retinal ganglion cells (hRGCs) within the host retina. Here, we demonstrated the pivotal role of host retinal microglia/macrophages in the rejection, acceptance and survival of donor cells. To explore the interaction between microglia and RGCs and to identify the targets for potential treatment, we utilized our previously assembled set of single-cell atlases for mouse retina. The downstream analysis has highlighted a phagocytosis among other known pathways involved in microglia activation, neuroinflammation and host retinal ganglion cell damage. We showed the possibility to improve the survival of donor human stem cell-derived retinal ganglion cells through modulation of the host retinal microglia. Pretreatment of donor human retinal ganglion cells with annexin V before transplantation leads to a 2.5-fold increase in donor cell short-term survival and axon outgrowth targeting optic nerve head (ONH). In addition, pretreatment of donor hRGCs with annexin V and soluble Fas ligand (sFasL) improves the retention of donor hRGCs within the retina following transplantation.