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    RPE Subpopulations Discovered and Mapped

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    Scientists at the NEI have identified five distinct retinal pigment epithelial (RPE) subpopulations and created a complete single-cell–resolution morphomet­ric map of their location in the eye.1 Their discovery demonstrates why different retinal degenerative dis­eases affect different parts of the eye, and it may lead to targeted therapies.

    Harnessing AI. The researchers used artificial intelligence (AI)-based software to analyze RPE cell morphometry from nine healthy human cadaver eyes. This analysis produced heatmap images of the entire epithelium. These images visually displayed the quan­tification of four shape metrics: cell area, aspect ratio, hexagonality, and number of neighbors.

    Creating a map. The AI-generated cell area maps revealed five RPE subpopulations organized in concen­tric circles around the fovea:

    • P1 roughly corresponds to the fovea and parafovea,
    • P2 covers most of the center of the RPE monolayer, including the perifovea,
    • P3 consists of a midperipheral ring of RPE cells,
    • P4 is a ring of small RPE cells of the periphery of the eye that is similar in cell size to RPE in and around the macula, and
    • P5 comprises far-peripheral RPE cells.

    A surprise subpopulation. With regard to P4, said coauthor Kapil Bharti, PhD, “The presence of a mac­ular-like subpopulation in the far periphery was a surprise.” Lead author Davide Ortolan, PhD, added, “The gene expression profile of this population seems similar to macular cells—and under diseased conditions they behave similarly to macular cells, in that they have higher drusen deposits and higher density of chorio­capillaris atrophy.” Understanding how those RPE cells in the far periphery interact with photoreceptors may lead to a better understanding of how peripheral vision works, they noted.

    Putting the map to work. First, the reference map allowed the scientists to analyze RPE from a second set of five cadaver eyes with AMD. In all of these eyes, RPE cells were lost due to disease damage in subpopulation P1 and up to the center of P2. In addition, large areas of geographic atrophy were visible at the far periphery of P4 and P5, often extending into P3.

    Second, to test the hypothesis that different types of retinal degeneration (RD) affect specific RPE sub­populations, the researchers analyzed ultra-widefield fundus images of patients with choroideremia (CHM), late-onset RD (L-ORD), and RDs with no identified molecular cause. P1 was relatively spared in these diseases, but midperipheral RPE subpopulations con­tained areas of RPE atrophy. Overall, P1, P4, and P5 appeared mostly affected in eyes with AMD, while P3 appeared to degenerate before the other subpopula­tions in patients with L-ORD, CHM, and RD.

    Clinical implications. These findings may provide a better understanding of AMD pathogenesis and, even­tually, pinpoint the location of endogenous RPE stem cells that have been suggested to be present in human eye but not yet confirmed, said Dr. Bharti.

    The authors are already using the AI-generated reference map to produce macular- and midperiph­ery-specific RPE cells. “We are a stem cell–based lab, and we are very good at making RPE cells from human stem cells,” Dr. Bharti said. “Now we will try to make the different RPE subpopulations and then use them to develop disease-specific cell and gene therapies.”

    —Miriam Karmel


    1 Ortolan D et al. Proc Natl Acad Sci. 2022;119(19):e2117553119.


    Relevant financial disclosures—Drs. Bharti and Ortolan: None.

    For full disclosures and the disclosure key, see below.

    Full Financial Disclosures

    Dr. Bharti None.

    Dr. Mueller None.

    Dr. Organ None.

    Dr. Pierscionek National Natural Science Foundation of China: S; NIH: S; SPring-8 Synchrotron: S.

    Dr. Thee None.

    Dr. Vergroesen None.

    Disclosure Category



    Consultant/Advisor C Consultant fee, paid advisory boards, or fees for attending a meeting.
    Employee E Hired to work for compensation or received a W2 from a company.
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    Owner of company EO Ownership or controlling interest in a company, other than stock.
    Independent contractor I Contracted work, including contracted research.
    Lecture fees/Speakers bureau L Lecture fees or honoraria, travel fees or reimbursements when speaking at the invitation of a commercial company.
    Patents/Royalty P Beneficiary of patents and/or royalties for intellectual property.
    Equity/Stock/Stock options holder, private corporation PS Equity ownership, stock and/or stock options in privately owned firms, excluding mutual funds.
    Grant support S Grant support or other financial support from all sources, including research support from government agencies (e.g., NIH), foundations, device manufacturers, and\or pharmaceutical companies. Research funding should be disclosed by the principal or named investigator even if your institution receives the grant and manages the funds.
    Stock options, public or private corporation SO Stock options in a public or private company.
    Equity/Stock holder, public corporation US Equity ownership or stock in publicly traded firms, excluding mutual funds (listed on the stock exchange).


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