Dynamic Transcriptomic Remodeling in Grafted Human Neural Progenitor Cells Uncovers Mechanisms for Vision Preservation in Retinitis Pigmentosa

Human neural progenitor cells (hNPCs) show promise in slowing retinal degeneration and are currently being tested in clinical trials for retinitis pigmentosa (RP). However, the long-term fate of grafted hNPCs and their interaction with host retinal cells remains unclear. Here, we used single-cell transcriptomics to investigate temporal gene expression changes in grafted hNPCs and host retinal cells following subretinal injection into a rodent model of RP, revealing dynamic transcriptomic changes in the degenerative retinal environment. Grafted hNPCs primarily differentiate into an astroglial phenotype and mature over time, contributing to photoreceptor protection through trophic factor secretion, metabolic modulation, suppression of apoptosis, oxidative stress, and inflammation, alongside extracellular matrix remodeling. CellChat analysis revealed a decline in intercellular signaling and communication strength over time, correlating with weakened hNPC-host interactions. These findings suggest that enhancing trophic factor support, particularly MANF, and improving the host retinal environment are critical for sustaining long-term vision preservation. Overall design: Following hNPC treatment, rats were sacrificed and retinas were dissected at postnatal days 60 (P60) and 90 (P90). Grafted hNPCs and host retinal cells were isolated by FACS and analyzed using single-cell RNA sequencing. Pre-grafted hNPCs were also sequenced as a control for the grafted hNPCs. Single-cell RNA sequencing data (samples GSM6403183 & GSM640318) from rat retinas from another study (Series GSE209872) were used as a non-disease controls. *************************************************************** The table below lists GEO accessions reused/reanalyzed for this study. ***************************************************************