ABSTRACT
The human retina is a complex neural tissue that detects light and sends visual information to the brain. However, the molecular and cellular processes that underlie aging primate retina remain unclear. Here, we provide a comprehensive transcriptomic atlas based on 119 520 single cells of the foveal and peripheral retina of humans and macaques covering different ages. The molecular features of retinal cells differed between the two species, suggesting distinct regional and species specializations of the human and macaque retinae. In addition, human retinal aging occurred in a region- and cell-type-specific manner. Aging of human retina exhibited a foveal to peripheral gradient. MYO9A- rods and a horizontal cell subtype were greatly reduced in aging retina, indicating their vulnerability to aging. Moreover, we generated a dataset showing the cell-type- and region-specific gene expression associated with 55 types of human retinal disease, which provides a foundation to understanding of the molecular and cellular mechanisms underlying human retinal diseases. Such datasets are valuable to understanding of the molecular characteristics of primate retina, as well as molecular regulation of aging progression and related diseases.
ABSTRACT
The development of single-cell RNA sequencing (scRNA-seq) has allowed high-resolution analysis of cell-type diversity and transcriptional networks controlling cell-fate specification. To identify the transcriptional networks governing human retinal development, we performed scRNA-seq analysis on 16 time points from developing retina as well as four early stages of retinal organoid differentiation. We identified evolutionarily conserved patterns of gene expression during retinal progenitor maturation and specification of all seven major retinal cell types. Furthermore, we identified gene-expression differences between developing macula and periphery and between distinct populations of horizontal cells. We also identified species-specific patterns of gene expression during human and mouse retinal development. Finally, we identified an unexpected role for ATOH7 expression in regulation of photoreceptor specification during late retinogenesis. These results provide a roadmap to future studies of human retinal development and may help guide the design of cell-based therapies for treating retinal dystrophies.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Biological Evolution , Gene Expression Regulation, Developmental , Organogenesis , Retina/cytology , Retinal Cone Photoreceptor Cells/metabolism , Single-Cell Analysis/methods , Aged, 80 and over , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Differentiation , Female , Humans , Mice , Retina/metabolism , Retinal Cone Photoreceptor Cells/cytology , Species SpecificityABSTRACT
Retinal organoids (ROs) derived from human induced pluripotent stem cells (hiPSCs) provide potential opportunities for studying human retinal development and disorders; however, to what extent ROs recapitulate the epigenetic features of human retinal development is unknown. In this study, we systematically profiled chromatin accessibility and transcriptional dynamics over long-term human retinal and RO development. Our results showed that ROs recapitulated the human retinogenesis to a great extent, but divergent chromatin features were also discovered. We further reconstructed the transcriptional regulatory network governing human and RO retinogenesis in vivo. Notably, NFIB and THRA were identified as regulators in human retinal development. The chromatin modifications between developing human and mouse retina were also cross-analyzed. Notably, we revealed an enriched bivalent modification of H3K4me3 and H3K27me3 in human but not in murine retinogenesis, suggesting a more dedicated epigenetic regulation on human genome.
