Migration, Integration and Maturation of Photoreceptor Precursors Following Transplantation in the Mouse Retina

Abstract

Retinal degeneration leading to loss of photoreceptors is a major cause of untreatable blindness. Recent research has yielded definitive evidence for restoration of vision following the transplantation of rod photoreceptors in murine models of blindness, while advances in stem cell biology have enabled the generation of transplantable photoreceptors from embryonic stem cells. Importantly, the amount of visual function restored is dependent upon the number of photoreceptors that migrate correctly into the recipient retina. The developmental stage of the donor cells is important for their ability to migrate; they must be immature photoreceptor precursors. Little is known about how and when donor cell migration, integration, and maturation occurs. Here, we have performed a comprehensive histological analysis of the 6-week period following rod transplantation in mice. Donor cells migrate predominately as single entities during the first week undergoing a stereotyped sequence of morphological changes in their translocation from the site of transplantation, through the interphotoreceptor matrix and into the recipient retina. This includes initial polarization toward the outer nuclear layer (ONL), followed by formation of an apical attachment and rudimentary segment during migration into the ONL. Strikingly, acquisition of a nuclear architecture typical of mature rods was accelerated compared with normal development and a feature of migrating cells. Once within the ONL, precursors formed synaptic-like structures and outer segments in accordance with normal maturation. The restoration of visual function mediated by transplanted photoreceptors correlated with the later expression of rod a-transducin, achieving maximal function by 5 weeks.

Pluripotent Stem Cell-Based Therapies in Combination with Substrate for the Treatment of Age-Related Macular Degeneration

“…A plethora of protocols describe photoreceptor differentiation from hESCs, and hESCderived retinal progenitors can integrate with host neural tissue and restore some visual response in blind mice. 36,45,[100][101][102] However, photoreceptors cannot be restored in AMD patients unless the underlying RPE is also functional. Therefore, to rescue photoreceptors and RPE in late AMD patients, scaffolds supporting both cell types must be designed.…”

Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial solutions

“…Rod precursors have been shown to migrate into the ONL, form new synaptic connections and outer segments [145,147,182,183], and even restore rod-mediated vision in mouse models of retinal degeneration [145,146].…”

Enhanced Functional Integration of Human Photoreceptor Precursors into Human and Rodent Retina in anEx VivoRetinal Explant Model System

“…31 We therefore used an endpoint of 7 days to study functional integration of PPCs in our coculture system (neurosensory retina on top of hESCderived pigment epithelial cells). We chose as our functional endpoint and sign of PPC-retinal integration the expression of proteins important in the development of ribbon synapses.…”