The human retinal pigment epithelium has five morphometrically distinct subpopulations which present differential disease vulnerability

Abstract

Purpose : Retinal pigment epithelium (RPE) cells present geographical differences across human eyes. In the macula, RPE cells are smaller in size and present distinct shapes of apical processes, in comparison to peripheral RPE. In addition, there are functional and molecular differences in these two RPE populations, such as RPE metabolism and expression of specific transporters. Moreover, selective death of macular RPE cells occurs during retinal degenerative diseases, such as age-related macular degeneration (AMD). Currently, there is no thorough description of human regional RPE diversity and vulnerability, thus limiting the understanding of regional degenerative diseases. This study aims to provide a detailed and comprehensive morphometric map of the entire human RPE.

Methods : RPE/choroid flatmounts were generated from more than 20 human non-AMD and AMD eyes. The entire flatmounts were stained for RPE cell borders and imaged. An open-source software for image analysis, based on machine learning, was developed to quantify RPE morphometry. Spreadsheets with raw data and color-coded images were generated to compare regional RPE differences.

Results : Human RPE cell shape analysis of non-AMD eyes revealed the presence of 5 morphometrically different RPE subpopulations, which we named as P1 to P5, going from the macula toward the periphery. RPE cell area increases with eccentricity; in the mid-periphery (P3), RPE cells are almost double the size of macular RPE (P1) (median: 238.7 µm² (± 18.9 µm² sd) vs 149.6 µm² (± 16.7 µm² sd)). In addition, a peripheral ring of smaller RPE cells (P4) was discovered (median: 181.8 µm² (± 19.8 µm² sd)). So far, the nature of P4 population remains elusive. RPE lesions were detected in the periphery of non-AMD eyes, revealing selective vulnerability of peripheral RPE populations (P4 and P5). Quantification of RPE lesions from AMD eyes and ultra-widefield retinal images of patients with monogenic disorders shows differential susceptibility of RPE subpopulations to degeneration.

Conclusions : Overall, the study provides the first comprehensive morphometric map of the human RPE and it provides a geographic reference of RPE subpopulations for other researchers in the field. Finally, studying the nature of each RPE subpopulation might help to understand regional retinal degeneration.

This is a 2021 ARVO Annual Meeting abstract.