Glaucoma and other optic neuropathies lead to the permanent loss of retinal ganglion cells (RGCs). Cell transplantation and transdifferentiation strategies have been proposed to restore RGCs, but one of the significant barriers to successful RGC integration into the existing retinal circuitry is cell migration toward their natural position in the retina. Here we describe a framework for identifying, selecting, and applying chemokines to direct cell migration in vivo within the retina. To identify chemokine targets, we perform an in silico analysis of the developing human retina’s single-cell transcriptome. From this analysis, we identified six receptor-ligand pairs that could potentially direct stem cell-derived or newborn neuron migration. These lead candidates were then tested in functional in vitro assays for their ability to guide stem cell-derived RGCs. To direct cell migration in vivo, we 1) delivered stem cell-derived donor RGC subretinally, or 2) reprogrammed RGC-like neurons in situ and injected SDF1 intravitreally – establishing a chemokine gradient across the retina. Our results demonstrated that an SDF1 gradient across the retina substantially enhanced the migration of donor RGCs into the ganglion cell layer and also facilitated the exit of newborn RGCs from the inner nuclear layer. Furthermore, by altering the migratory profile of donor RGCs toward multipolar migration, overall migration was improved in mature neural tissues. Taken together, our findings underscore the value and potential of manipulating both the tissue microenvironment and the cells themselves. This work lays the groundwork for future research and clinical applications in gene and cell therapies aimed at treating retinal disorders.

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