Developing a Macular Region in Stem Cell-Derived Retinal Organoids

Abstract

Purpose : The macula is a specialised region of the human retina, distinguished by its dense population of cone photoreceptor cells responsible for our central, colour vision and visual acuity. Non-primate animal models lack a macula, making studying this region difficult. Retinal organoids derived from pluripotent stem cells (PSCs) offer a human platform to better understand development, diseases, and therapeutics; however, retinal organoids have not yet developed a typical macular region.

Methods : Not much is known about the specific signalling pathways involved in the development of the human macula. Here, we use Spatial Transcriptomics (10x Genomics) to elucidate transcriptomic differences between the peripheral and central regions of 9-10-week-old PSC-derived retinal organoids.
RA signalling is a pathway that has been explored and implicated in the development of the chick's high visual acuity area, a structure analogous to the human fovea. We explored the effect these signalling molecules had on retinogenesis and retinal organoid maturation.

Results : This developmental period of 9-10-week-old organoids highlights the peripheral versus central retina with the distribution of retinal progenitors, early-born ganglion cells and cone photoreceptors. This data provides numerous insights into organoid development, such as the distribution of retinoic acid (RA) signalling enzymes.
Organoids deprived of RA showed a significant increase in the relative number of ARRESTIN3 and L/M-Opsin positive cone photoreceptor cells. This increase was accompanied by a significant decrease in rod cells and an early increase in S-Opsin positive cones, although this was lost at later time points. Furthermore, we detected an earlier genesis of L/M-opsin-positive outer segments in mature organoids that did not receive RA. Together, these results indicate the wide-ranging effects that RA has on photoreceptor cell fate and maturation.

Conclusions : This data highlights how these signalling pathways are integral to retinal development and contribute to our understanding of cone photoreceptor cells, the most prevalent cell type in the macula. This provides a foothold to recapitulate the macula in human retinal organoids.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.