June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Cone photoreceptors in human retinal organoids demonstrate robust light-evoked function.
Author Affiliations & Notes
  • Aindrila Saha
    Neuroscience, University of Wisconsin System, Madison, Wisconsin, United States
    McPherson Eye Research Institute, University of Wisconsin System, Madison, Wisconsin, United States
  • Elizabeth Capowski
    McPherson Eye Research Institute, University of Wisconsin System, Madison, Wisconsin, United States
    Waisman Center, University of Wisconsin System, Madison, Wisconsin, United States
  • David Gamm
    Ophthalmology and Visual Sciences, University of Wisconsin System, Madison, Wisconsin, United States
    McPherson Eye Research Institute, University of Wisconsin System, Madison, Wisconsin, United States
  • Raunak Sinha
    Neuroscience, University of Wisconsin System, Madison, Wisconsin, United States
    Ophthalmology and Visual Sciences, University of Wisconsin System, Madison, Wisconsin, United States
  • Footnotes
    Commercial Relationships   Aindrila Saha, None; Elizabeth Capowski, None; David Gamm, Opsis Therapeutics LLC (S), US Patent No US9752119B2 (P); Raunak Sinha, None
  • Footnotes
    Support  NIH grant EY026070, BrightFocus Foundation (macular degeneration grant): M2019131, Alcon Research Institute young investigator grant, McPherson Eye Research Institute, Wisconsin National Primate Research Center Pilot Grant, Retina Research Foundation and McPherson Eye Research Institute Sandra Lemke Trout Chair in Eye Research.
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1664. doi:
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    • Get Citation

      Aindrila Saha, Elizabeth Capowski, David Gamm, Raunak Sinha; Cone photoreceptors in human retinal organoids demonstrate robust light-evoked function.. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1664.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The first step of our high-definition central vision occurs in the cone photoreceptors in the fovea, which are tightly packed forming a dense pixel array capable of resolving fine spatial details. Death of foveal cones is the ultimate cause of central vision loss in age-related macular degeneration – a leading cause of blindness – as well as other acquired and inherited retinal degenerative diseases. Although human pluripotent stem-cell (hPSC) based replacement strategies hold promise for vision restoration in such conditions, its effective application is limited due to i) a sparse understanding of cone signaling in the primate fovea and ii) a lack of evidence that organoid cones (OCs) can exhibit light-evoked function similar to primate cones in vivo. In this study, we use primate foveal cones (FCs) as a baseline to compare the light-evoked physiology of OCs.

Methods : We used patch-clamp electrophysiology to record light-evoked responses from >100 cones across several hPSC-derived organoids (differentiated >200 days in vitro) and macaque fovea. We compared the photo-responses and membrane properties of the OCs with that of FCs.

Results : Recordings from individual OCs show robust light-evoked responses from a sizeable fraction of OCs across hPSC-organoids. OCs of different spectral types could be identified, though most of them show mid-wavelength spectral sensitivity. The response shape to brief light flashes show profiles similar to that of adult FCs. The light responses of OCs also demonstrate adaptation at higher background luminance similar to typical cones. Both the size and kinetics of light responses in OCs show variability within and between organoids. Although some of the membrane properties of OCs are comparable with that of adult FCs, a few resemble fetal FCs. These findings provide evidence that OCs mimic several physiological properties of adult FCs.

Conclusions : Our recordings from OCs show physiological light-evoked responses over a wide range of light levels. In addition, we were able to replicate several key features of primate FC photo-responses in OCs. These results provide a crucial first step in establishing hPSC-organoids as sources of bona fide human cones and as model systems for drug testing and for studying deficits in photoreceptor physiology in acquired and inherited macular degenerative diseases and cone and cone-rod dystrophies.

This is a 2021 ARVO Annual Meeting abstract.

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