Photoreceptor loss due to degenerative retinopathy is a leading cause of adult vision loss. Transplantation of photoreceptor precursor cells (PPCs) into adult retina is an exciting strategy for replacing lost photoreceptors and restoring vision in mice. However, a major obstacle to advancement of this approach is extremely limited migration of transplanted cells through the interphotoreceptor matrix (IPM) and into the retina. Our laboratory has discovered, that PPCs express a number of migratory receptors which guide migration to retinal ligands in vitro. We hypothesize that receptor-driven, haptotactic and chemotactic mechanisms can be exploited to optimize PPC migration through the IPM and into the retina. Our first goal in this project is to characterize PPC haptotaxis to bound IPM ligands and chemotaxis to soluble retinal ligands using our established bioinformatics database and microfluidics platform. We will characterize chemotaxis driven by the top three expressed PPC receptors to their corresponding soluble retinal ligands, KDR-VEGF, PDGFR-PDGF, and RET-GDNF, receptors-ligands respectively. And we will analyze haptotaxis driven by the top two haptotactic PPC receptors ITGAM and ITGB1 to IPM ligands chondroitin sulfate and fibronectin. Next, we will examine the extent to which modulation of haptotactic and chemotactic receptors will increase migration in vitro and in a rhodopsin knockout, degenerative retinopathy retina model ex vivo. Lastly, we will analyze receptor protein levels of PPCs migrated into the IPM and retina to validate our current data and define novel mechanisms of PPC migration. The combined cross-disciplinary approach will provide data to move PPC transplantation forward for the restoration of vision.
and Impact to Human Health Photoreceptor loss due to degenerative retinopathy is a leading cause of adult vision loss worldwide. Transplantation of photoreceptor precursor cells (PPCs) into the degenerative retina is an exciting strategy for replacing lost photoreceptors and restoring vision. This project aims to define and optimize the cellular mechanisms driving PPC migration into the retina for photoreceptor repopulation and vison restoration.
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