Deciphering the spatio-temporal transcriptional and chromatin accessibility of human retinal organoid development at the single cell level

Abstract

Molecular information on the early stages of human retinal development remains scarce due to limitations in obtaining early human eye samples. Pluripotent stem cell-derived retinal organoids provide an unprecedented opportunity for studying early retinogenesis. Using a combination of single cell RNA-Seq and spatial transcriptomics we present for the first-time a single cell spatio-temporal transcriptome of retinal organoid development. Our data demonstrate that retinal organoids recapitulate key events of retinogenesis including optic vesicle/cup formation, formation of a putative ciliary margin zone, emergence of retinal progenitor cells and their orderly differentiation to retinal neurons. Combining the scRNA- with scATAC-Seq data, we were able to reveal cell-type specific transcription factor binding motifs on accessible chromatin at each stage of organoid development and to show that chromatin accessibility is highly correlated to the developing human retina, but with some differences in the temporal emergence and abundance of some of the retinal neurons.

Effective AAV-mediated gene replacement therapy in retinal organoids modeling AIPL1-associated LCA4

“…The lack of overt photoreceptor degeneration may be due to the fact that ROs faithfully recapitulate in utero retinogenesis with the transcriptional profile and retinal cells types of 38 week ROs closely resembling the new-born human retina. 28 , 29 , 30 , 31 , 32 While ROs mimic the developing human retina, we reported previously using high-resolution optical coherence tomography that the outer retina may be preserved in patients up to 1 year of age. 33 While the exact trigger for retinal degeneration has, therefore, yet to be determined, our transcriptomic data reveal intriguing clues as to the consequences of cGMP elevation preceding the onset of photoreceptor degeneration.…”