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      Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution

      research-article
      1 , 2 , 10 , 1 , 2 , 3 , 10 , 1 , 1 , 2 , 4 , 1 , 1 , 2 , 1 , 1 , 2 , 1 , 2 , 3 , 3 , 2 , 5 , 6 , 1 , 2 , 1 , 1 , 1 , 4 , 3 , 2 , 1 , 1 , 1 , 7 , 8 , 2 , 5 , 4 , 1 , 4 , 6 , 1 , 4 , 9 , 3 , , 3 , ∗∗ , 1 , 2 , 4 , 11 , ∗∗∗
      Cell
      Cell Press
      organoid, retina, single cell sequencing, transcriptome, eye disease, retinal organoid, macular degeneration, organoid development, human retina, synaptic function

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers and functional synapses. We sequenced the RNA of 285,441 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable “developed” state at a rate similar to human retina development in vivo. Transcriptomes of organoid cell types converged toward the transcriptomes of adult peripheral retinal cell types. Expression of disease-associated genes was cell-type-specific in adult retina, and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas.

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          Highlights

          • Light-sensitive, multilayered human retinal organoids with functional synapses

          • 285,441 transcriptomes from light-responsive human retinas and retinal organoids

          • Organoid cell types converge to adult peripheral retinal cell types

          • Linking retinal diseases to human retinal and retinal organoid cell types

          Abstract

          Light-sensitive, multilayered human retinal organoids with functional synapses are developed and benchmarked against human retinas obtained under conditions that preserve retinal integrity.

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          Most cited references43

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          High-performance calcium sensors for imaging activity in neuronal populations and microcompartments

          Calcium imaging with genetically encoded calcium indicators (GECIs) is routinely used to measure neural activity in intact nervous systems. GECIs are frequently used in one of two different modes: to track activity in large populations of neuronal cell bodies, or to follow dynamics in subcellular compartments such as axons, dendrites and individual synaptic compartments. Despite major advances, calcium imaging is still limited by the biophysical properties of existing GECIs, including affinity, signal-to-noise ratio, rise and decay kinetics and dynamic range. Using structure-guided mutagenesis and neuron-based screening, we optimized the green fluorescent protein-based GECI GCaMP6 for different modes of in vivo imaging. The resulting jGCaMP7 sensors provide improved detection of individual spikes (jGCaMP7s,f), imaging in neurites and neuropil (jGCaMP7b), and may allow tracking larger populations of neurons using two-photon (jGCaMP7s,f) or wide-field (jGCaMP7c) imaging.
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            Retinal ischemia: mechanisms of damage and potential therapeutic strategies.

            Retinal ischemia is a common cause of visual impairment and blindness. At the cellular level, ischemic retinal injury consists of a self-reinforcing destructive cascade involving neuronal depolarisation, calcium influx and oxidative stress initiated by energy failure and increased glutamatergic stimulation. There is a cell-specific sensitivity to ischemic injury which may reflect variability in the balance of excitatory and inhibitory neurotransmitter receptors on a given cell. A number of animal models and analytical techniques have been used to study retinal ischemia, and an increasing number of treatments have been shown to interrupt the "ischemic cascade" and attenuate the detrimental effects of retinal ischemia. Thus far, however, success in the laboratory has not been translated to the clinic. Difficulties with the route of administration, dosage, and adverse effects may render certain experimental treatments clinically unusable. Furthermore, neuroprotection-based treatment strategies for stroke have so far been disappointing. However, compared to the brain, the retina exhibits a remarkable natural resistance to ischemic injury, which may reflect its peculiar metabolism and unique environment. Given the increasing understanding of the events involved in ischemic neuronal injury it is hoped that clinically effective treatments for retinal ischemia will soon be available.
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              CaImAn an open source tool for scalable calcium imaging data analysis

              Advances in fluorescence microscopy enable monitoring larger brain areas in-vivo with finer time resolution. The resulting data rates require reproducible analysis pipelines that are reliable, fully automated, and scalable to datasets generated over the course of months. We present CaImAn, an open-source library for calcium imaging data analysis. CaImAn provides automatic and scalable methods to address problems common to pre-processing, including motion correction, neural activity identification, and registration across different sessions of data collection. It does this while requiring minimal user intervention, with good scalability on computers ranging from laptops to high-performance computing clusters. CaImAn is suitable for two-photon and one-photon imaging, and also enables real-time analysis on streaming data. To benchmark the performance of CaImAn we collected and combined a corpus of manual annotations from multiple labelers on nine mouse two-photon datasets. We demonstrate that CaImAn achieves near-human performance in detecting locations of active neurons.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                17 September 2020
                17 September 2020
                : 182
                : 6
                : 1623-1640.e34
                Affiliations
                [1 ]Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland
                [2 ]Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland
                [3 ]Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
                [4 ]Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland
                [5 ]Swiss Institute of Bioinformatics, 4058 Basel, Switzerland
                [6 ]Bio Engineering Laboratory, Department of Biosystems Science and Engineering of ETH Zurich, 4058 Basel, Switzerland
                [7 ]Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary
                [8 ]Department of Anatomy, Histology and Embryology, Semmelweis University, 1085 Budapest, Hungary
                [9 ]Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21287, USA
                Author notes
                []Corresponding author guglielmo.roma@ 123456novartis.com
                [∗∗ ]Corresponding author florian.nigsch@ 123456novartis.com
                [∗∗∗ ]Corresponding author botond.roska@ 123456iob.ch
                [10]

                These authors contributed equally

                [11]

                Lead Contact

                Article
                S0092-8674(20)31004-7
                10.1016/j.cell.2020.08.013
                7505495
                32946783
                4bcaa62f-7b85-4301-ba07-0b9b3fd0a8d6
                © 2020 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 July 2019
                : 14 June 2020
                : 6 August 2020
                Categories
                Resource

                Cell biology
                organoid,retina,single cell sequencing,transcriptome,eye disease,retinal organoid,macular degeneration,organoid development,human retina,synaptic function

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