Lineage tracing reveals photoreceptor precursor cell subpopulations that contribute to murine retinogenesis

Cell-based therapies hold great promise for treating late-stage retinal degenerative diseases. However, photoreceptor cell transplantation has been limited by poor cellular integration, suggesting that an ideal population of donor cells has not yet been defined. Here, we utilized single-cell RNA-sequencing to assess the heterogeneity of photoreceptor precursor cells during murine retinal development. Subgroup analysis revealed three transcriptionally and spatially distinct populations of Crx+ cells from postnatal day 2-6 retinas which are consistent with early (Dll1+), intermediate (Neurod4+), and late (Prom1+) photoreceptor precursor cells. Lineage tracing with subpopulation-specific Cre mice showed that Dll1+, Neurod4+, and Prom1+ cells all generate photoreceptor cells but exhibit a spectrum of developmental plasticity. Transcriptomic analysis revealed that homologous CRX+ subpopulations are present in maturing human retinal organoids. These findings highlight the heterogeneity of neonatal photoreceptor precursor cells, and could help inform future strategies to isolate an optimal population of cells for retinal regeneration.