Retinal cell map could advance precise therapies for blinding diseases

Press release

Friday, May 6, 2022

NIH discovery sheds light on tissues targeted by age-related macular degeneration and other diseases.

Researchers have identified distinct differences between the cells that make up retinal tissue that is vital for human visual perception. National Eye Institute (NEI) scientists have discovered five subpopulations of the retinal pigment epithelium (RPE), a layer of tissue that nourishes and supports the retina’s light-sensitive photoreceptors. Using artificial intelligence, the researchers analyzed single-cell resolution RPE images to create a reference map that locates each subpopulation in the eye. A report on the research published in Proceedings of the National Academy of Sciences.

“These findings provide a unique framework for understanding different RPE cell subpopulations and their susceptibility to retinal diseases, and for developing targeted therapies to treat them,” said NEI Director Michael F. Chiang, MD, part of the National Institutes of Health.

“The results will help us develop more precise cell and gene therapies for specific degenerative eye diseases,” said the study’s principal investigator, Kapil Bharti, Ph.D., who leads the cell translational research section. oculars and strains of NEI.

Vision begins when light strikes the rod- and cone-shaped photoreceptors that line the retina at the back of the eye. Once activated, photoreceptors send signals through a complex network of other retinal neurons that converge on the optic nerve before traveling to various centers in the brain. The RPE lies beneath the photoreceptors as a monolayer, one cell deep.

Age and disease can cause metabolic changes in RPE cells that can lead to photoreceptor degeneration. The impact on vision of these RPE changes varies widely depending on the severity and where the RPE cells reside in the retina. For example, late-onset retinal degeneration (L-ORD) primarily affects the peripheral retina and, therefore, peripheral vision. Age-related macular degeneration (AMD), one of the leading causes of vision loss, primarily affects the RPE cells in the macula, which are crucial for central vision.

Bharti and colleagues sought to determine if there are different subpopulations of RPEs that could explain the wide range of retinal disease phenotypes.

The team used artificial intelligence (AI) to analyze RPE cell morphometry, the external shape and dimensions of each cell. They trained a computer using fluorescently labeled RPE images to analyze the entire human RPE monolayer from nine cadaveric donors with no history of significant eye disease.

Morphometric characteristics were calculated for each RPE cell – on average, approximately 2.8 million cells per donor; 47.6 million cells were analyzed in total. The algorithm evaluated the area of ​​each cell, the aspect ratio (width to height), the hexagon and the number of neighbors. Previous studies have suggested that RPE function is related to the tightness of cell junctions; the more people, the better to indicate cellular health.

Based on morphometry, they identified five distinct subpopulations of RPE cells, called P1-P5, organized in concentric circles around the fovea, which is the center of the macula and the most light-sensitive region of the retina. Compared to peripheral RPE, foveal RPE tends to be perfectly hexagonal and more compactly located, with a higher number of neighboring cells.

Unexpectedly, they found that the peripheral retina contains a ring of RPE cells (P4) with a cell area very similar to RPE in and around the macula.

“The presence of the P4 subpopulation highlights diversity within the retinal periphery, suggesting that there may be functional differences among RPEs that we are currently unaware of,” said the first author of the paper. study, Davide Ortolan, Ph.D. associate researcher in NEI’s Ocular and Stem Cell Translational Research Section. “Future studies are needed to help us understand the role of this subpopulation.”

Then they analyzed the EPR of cadavers with AMD. Foveal RPE (P1) tended to be absent due to disease damage, and differences between cells in the P2-P5 subpopulations were not statistically significant. Overall, AMD RPE subpopulations tended to be elongated compared to RPE cells unaffected by AMD.

To further test the hypothesis that different retinal degenerations affect specific RPE subpopulations, they analyzed ultra-widefield fundus autofluorescence images of patients with choroideremia, L-ORD or retinal degeneration with no identified molecular cause. Although these studies were conducted at one time, they still demonstrated that different RPE subpopulations are vulnerable to different types of retinal degenerative diseases.

“Overall, the results suggest that AI can detect changes in RPE cell morphometry prior to the development of visibly apparent degeneration,” Ortolan said.

Age-related morphometric changes may also appear in some RPE subpopulations before being detectable in others. These findings will help inform future studies using noninvasive imaging technologies, such as adaptive optics, which resolve retinal cells in unprecedented detail and could potentially be used to predict changes in RPE health. in living patients.

The study was funded by the NEI Intramural Research Program.

This press release describes a basic research result. Basic research improves our understanding of human behavior and biology, which is fundamental to advancing new and better ways to prevent, diagnose and treat disease. Science is an unpredictable and incremental process – every advance in research builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit https://www.nih.gov/news-events/basic-research-digital-media-kit.

NEI leads federal government research on the visual system and eye disease. NEI supports basic and clinical science programs to develop sight-saving treatments and address the special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH):The NIH, the country’s medical research agency, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.

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References

Ortolan D, Sharma R, Volkov A, Maminishkis A, Hotaling NA, Huryn LA, Cukras C, Di Marco S, Bisti S, Bharti K. “Single Cell Resolution Map of Human Retinal Pigment Epithelium Uncovers Sub -populations with differential susceptibility to disease”. PNAS. https://doi.org/10.1073/pnas.2117553119

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