Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution

TLDR

Human organoids that recapitulate the cell‑type diversity and function of their target organ are valuable for basic and translational research. The study develops light‑sensitive human retinal organoids that contain multiple nuclear and synaptic layers and functional synapses. The authors performed single‑cell RNA sequencing of 285,441 cells from organoids across seven developmental stages and from adult retinal regions, complemented by histochemical analysis. The organoids reached a stable, developmentally mature state comparable to the human retina, with cell‑type transcriptomes converging toward adult peripheral retinal profiles, preserving disease‑associated gene expression patterns, revealing unexpected disease‑related cell types such as those implicated in macular degeneration, and providing a resource for targeting disease mechanisms and repair.

Abstract

Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers and functional synapses. We sequenced the RNA of 285,441 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable "developed" state at a rate similar to human retina development in vivo. Transcriptomes of organoid cell types converged toward the transcriptomes of adult peripheral retinal cell types. Expression of disease-associated genes was cell-type-specific in adult retina, and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas.