A single‐cell transcriptome atlas of the adult human retina

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Abstract

The retina is a specialized neural tissue that senses light and initiates image processing. Although the functional organization of specific retina cells has been well studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile the human retina, we performed single‐cell RNA sequencing on 20,009 cells from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct cell populations representing all known neural retinal cells: rod photoreceptors, cone photoreceptors, Müller glia, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, astrocytes, and microglia. Our data captured molecular profiles for healthy and putative early degenerating rod photoreceptors, and revealed the loss of MALAT 1 expression with longer post‐mortem time, which potentially suggested a novel role of MALAT 1 in rod photoreceptor degeneration. We have demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell‐derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to understanding retinal biology and disease.

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Classification of low quality cells from single-cell RNA-seq data

Tomislav Ilicic, Jong Kim, Aleksandra A. Kolodziejczyk … (2016)

Single-cell RNA sequencing (scRNA-seq) has broad applications across biomedical research. One of the key challenges is to ensure that only single, live cells are included in downstream analysis, as the inclusion of compromised cells inevitably affects data interpretation. Here, we present a generic approach for processing scRNA-seq data and detecting low quality cells, using a curated set of over 20 biological and technical features. Our approach improves classification accuracy by over 30 % compared to traditional methods when tested on over 5,000 cells, including CD4+ T cells, bone marrow dendritic cells, and mouse embryonic stem cells. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-0888-1) contains supplementary material, which is available to authorized users.

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The arrangement of the three cone classes in the living human eye.

A Roorda, D R Williams (1999)

Human colour vision depends on three classes of receptor, the short- (S), medium- (M), and long- (L) wavelength-sensitive cones. These cone classes are interleaved in a single mosaic so that, at each point in the retina, only a single class of cone samples the retinal image. As a consequence, observers with normal trichromatic colour vision are necessarily colour blind on a local spatial scale. The limits this places on vision depend on the relative numbers and arrangement of cones. Although the topography of human S cones is known, the human L- and M-cone submosaics have resisted analysis. Adaptive optics, a technique used to overcome blur in ground-based telescopes, can also overcome blur in the eye, allowing the sharpest images ever taken of the living retina. Here we combine adaptive optics and retinal densitometry to obtain what are, to our knowledge, the first images of the arrangement of S, M and L cones in the living human eye. The proportion of L to M cones is strikingly different in two male subjects, each of whom has normal colour vision. The mosaics of both subjects have large patches in which either M or L cones are missing. This arrangement reduces the eye's ability to recover colour variations of high spatial frequency in the environment but may improve the recovery of luminance variations of high spatial frequency.

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A thyroid hormone receptor that is required for the development of green cone photoreceptors.

Neil Forrest, Leo B. Hurley, Shyam M. Srinivas … (2000)

Color vision is facilitated by distinct populations of cone photoreceptors in the retina. In rodents, cones expressing different opsin photopigments are sensitive to middle (M, 'green') and short (S, 'blue') wavelengths, and are differentially distributed across the retina. The mechanisms that control which opsin is expressed in a particular cone are poorly understood, but previous in vitro studies implicated thyroid hormone in cone differentiation. Thyroid hormone receptor beta 2 (TR beta 2) is a ligand-activated transcription factor that is expressed in the outer nuclear layer of the embryonic retina. Here we delete Thrb (encoding Tr beta 2) in mice, causing the selective loss of M-cones and a concomitant increase in S-opsin immunoreactive cones. Moreover, the gradient of cone distribution is disturbed, with S-cones becoming widespread across the retina. The results indicate that cone photoreceptors throughout the retina have the potential to follow a default S-cone pathway and reveal an essential role for Tr beta 2 in the commitment to an M-cone identity. Our findings raise the possibility that Thrb mutations may be associated with human cone disorders.

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Author and article information

Journal

Title: The EMBO Journal

Abbreviated Title: EMBO J

Publisher: EMBO

ISSN (Print): 0261-4189

ISSN (Electronic): 1460-2075

Publication date Created: August 22 2019

Publication date (Electronic): August 22 2019

Affiliations

[1 ]Institute for Molecular Bioscience University of Queensland Brisbane Qld Australia

[2 ]Monash University Melbourne Vic. Australia

[3 ]National Institute for Aging National Institutes of Health Baltimore MD USA

[4 ]Centre for Eye Research Australia Melbourne Vic. Australia

[5 ]Ophthalmology Department of Surgery University of Melbourne Melbourne Vic. Australia

[6 ]Jinan University Guangzhou China

[7 ]The University of Sydney Faculty of Medicine Save Sight Institute Sydney NSW Australia

[8 ]Garvan‐Weizmann Centre for Cellular Genomics Garvan Institute of Medical Research Sydney NSW Australia

[9 ]Australian Genome Research Facility Melbourne Vic. Australia

[10 ]Stem Cells and Regenerative Medicine Section NIHR Great Ormond Street Hospital Biomedical Research Centre UCL Great Ormond Street Institute of Child Health London UK

[11 ]Lions Eye Donation Services Melbourne Vic. Australia

[12 ]John Curtin School of Medical Research The Australian National University Canberra ACT Australia

[13 ]Department of Chemistry and Biotechnology Swinburne University of Technology Melbourne Vic. Australia

[14 ]Center for Human Tissues and Organs Degeneration Institute of Biomedicine and Biotechnology Shenzhen Institute of Advanced Technology Chinese Academy of Science Shenzhen China

[15 ]Menzies Institute for Medical Research University of Tasmania Hobart Tas. Australia

[16 ]UNSW Cellular Genomics Futures Institute University of New South Wales Sydney NSW Australia

[17 ]Shenzhen Eye Hospital Shenzhen University School of Medicine Shenzhen China

Article

DOI: 10.15252/embj.2018100811

PMC ID: 6745503

PubMed ID: 31436334

SO-VID: ce36f8a0-7e20-45ef-b895-5d432d3d8044

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http://doi.wiley.com/10.1002/tdm_license_1.1

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A single‐cell transcriptome atlas of the adult human retina

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Most cited references 33

Classification of low quality cells from single-cell RNA-seq data

The arrangement of the three cone classes in the living human eye.

A thyroid hormone receptor that is required for the development of green cone photoreceptors.

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