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Transcriptome-based molecular staging of human stem cell-derived retinal organoids uncovers accelerated photoreceptor differentiation by 9-cis retinal

Published in bioRxiv
· DOI :10.1101/733071
Koray Dogan Kaya6
Estimated H-index: 6
(NIH: National Institutes of Health),
Hsiu-Chuan Chen2
Estimated H-index: 2
(NIH: National Institutes of Health)
+ -3 AuthorsAnand Swaroop72
Estimated H-index: 72
(NIH: National Institutes of Health)
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Abstract
Retinal organoids generated from human pluripotent stem cells exhibit considerable variability in temporal dynamics of differentiation. To assess the maturity of neural retina in vitro, we performed transcriptome analyses of developing organoids from human embryonic and induced pluripotent stem cell lines. We show that the developmental variability in organoids was reflected in gene expression profiles and could be evaluated by molecular staging with the human fetal and adult retinal transcriptome data. We also demonstrated that addition of 9-cis retinal, instead of widely-used all-trans retinoic acid, accelerated rod photoreceptor differentiation in organoid cultures, with higher rhodopsin expression and more mature mitochondrial morphology evident by day 120. Our studies thus provide an objective transcriptome-based modality for determining the differentiation state of retinal organoids, which should facilitate disease modeling and evaluation of therapies in vitro.
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References68
Newest
Sangbae Kim1
Estimated H-index: 1
(BCM: Baylor College of Medicine),
Albert Lowe1
Estimated H-index: 1
(Albert Einstein College of Medicine)
+ 12 AuthorsDenise J. Morgan8
Estimated H-index: 8
(UofU: University of Utah)
Rod and cone photoreceptors are light-sensing cells in the human retina. Rods are dominant in the peripheral retina, whereas cones are enriched in the macula, which is responsible for central vision and visual acuity. Macular degenerations affect vision the most and are currently incurable. Here we report the generation, transcriptome profiling, and functional validation of cone-rich human retinal organoids differentiated from hESCs using an improved retinal differentiation system. Induced by ex...
Published on Mar 27, 2019in Stem Cells Translational Medicine5.96
Carla B. Mellough10
Estimated H-index: 10
(Newcastle University),
Joseph Collin9
Estimated H-index: 9
(Newcastle University)
+ 7 AuthorsMajlinda Lako43
Estimated H-index: 43
(Newcastle University)
Published on Jan 1, 2019in Development5.76
Elizabeth E. Capowski16
Estimated H-index: 16
(UW: University of Wisconsin-Madison),
Kayvan Samimi1
Estimated H-index: 1
(Morgridge Institute for Research)
+ 17 AuthorsLindsey D. Jager3
Estimated H-index: 3
(UW: University of Wisconsin-Madison)
ABSTRACT Numerous protocols have been described for producing neural retina from human pluripotent stem cells (hPSCs), many of which are based on the culture of 3D organoids. Although nearly all such methods yield at least partial segments of retinal structure with a mature appearance, variabilities exist within and between organoids that can change over a protracted time course of differentiation. Adding to this complexity are potential differences in the composition and configuration of retina...
Published on Oct 12, 2018in Science41.04
Kiara C. Eldred5
Estimated H-index: 5
(Johns Hopkins University),
Sarah E. Hadyniak1
Estimated H-index: 1
(Johns Hopkins University)
+ 10 AuthorsJames Taylor33
Estimated H-index: 33
(Johns Hopkins University)
INTRODUCTION Cone photoreceptors in the human retina enable daytime, color, and high-acuity vision. The three subtypes of human cones are defined by the visual pigment that they express: blue-opsin (short wavelength; S), green-opsin (medium wavelength; M), or red-opsin (long wavelength; L). Mutations that affect opsin expression or function cause various forms of color blindness and retinal degeneration. RATIONALE Our current understanding of the vertebrate eye has been derived primarily from th...
Published on Oct 1, 2018in Stem Cells5.61
Dean Hallam5
Estimated H-index: 5
(Newcastle University),
Gerrit Hilgen8
Estimated H-index: 8
(Newcastle University)
+ 15 AuthorsStefan Kustermann7
Estimated H-index: 7
(Hoffmann-La Roche)
This is an Open Access Article. It is published by AlphaMed Press under the Creative Commons Attribution 4.0 Unported Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/4.0/
Published on Oct 1, 2018in Current Opinion in Genetics & Development5.29
Nicolás M Ortega (KI: Karolinska Institutet), Nerges Winblad1
Estimated H-index: 1
(KI: Karolinska Institutet)
+ 1 AuthorsFredrik Lanner20
Estimated H-index: 20
(KI: Karolinska Institutet)
Understanding the genetic underpinning of early human development is of great interest not only for basic developmental and stem cell biology but also for regenerative medicine, infertility treatments, and better understanding the causes of congenital disease. Our current knowledge has mainly been generated with the use of laboratory animals, especially the mouse. While human and mouse early development present morphological resemblance, we know that the timing of the events as well as the cellu...
Published on Apr 1, 2018in Stem cell reports5.50
Wen-Li Deng3
Estimated H-index: 3
(WMU: Wenzhou Medical College),
Mei-Ling Gao3
Estimated H-index: 3
(WMU: Wenzhou Medical College)
+ 10 AuthorsYan-Ping Li1
Estimated H-index: 1
(WMU: Wenzhou Medical College)
Summary Retinitis pigmentosa (RP) is an irreversible, inherited retinopathy in which early-onset nyctalopia is observed. Despite the genetic heterogeneity of RP, RPGR mutations are the most common causes of this disease. Here, we generated induced pluripotent stem cells (iPSCs) from three RP patients with different frameshift mutations in the RPGR gene, which were then differentiated into retinal pigment epithelium (RPE) cells and well-structured retinal organoids possessing electrophysiological...
Published on Mar 1, 2018in Cell Reports7.82
Lu Wang2
Estimated H-index: 2
(St. Jude Children's Research Hospital),
Daniel Hiler4
Estimated H-index: 4
(St. Jude Children's Research Hospital)
+ 13 AuthorsAbbas Shirinifard12
Estimated H-index: 12
(St. Jude Children's Research Hospital)
Summary Diverse cell types can be reprogrammed into pluripotent stem cells by ectopic expression of Oct4 (Pou5f1), Klf4, Sox3, and Myc. Many of these induced pluripotent stem cells (iPSCs) retain memory, in terms of DNA methylation and histone modifications (epigenetic memory), of their cellular origins, and this may bias subsequent differentiation. Neurons are difficult to reprogram, and there has not been a systematic side-by-side characterization of reprogramming efficiency or epigenetic memo...
Published on Feb 1, 2018in Stem Cell Research3.93
Ana Artero Castro3
Estimated H-index: 3
,
Marian León3
Estimated H-index: 3
+ 2 AuthorsDunja Lukovic9
Estimated H-index: 9
Abstract The human iPSC cell line, derived from foreskin fibroblasts was generated by non-integrative, non-viral reprogramming technology using OCT4, SOX2, KLF4, LIN28, c-MYC mRNAs.
Published on Jan 1, 2018in Stem cell reports5.50
Tyler DiStefano2
Estimated H-index: 2
(NIH: National Institutes of Health),
Holly Yu Chen2
Estimated H-index: 2
(NIH: National Institutes of Health)
+ 6 AuthorsAnand Swaroop72
Estimated H-index: 72
(NIH: National Institutes of Health)
Summary Pluripotent stem cells can be differentiated into 3D retinal organoids, with major cell types self-patterning into a polarized, laminated architecture. In static cultures, organoid development may be hindered by limitations in diffusion of oxygen and nutrients. Herein, we report a bioprocess using rotating-wall vessel (RWV) bioreactors to culture retinal organoids derived from mouse pluripotent stem cells. Organoids in RWV demonstrate enhanced proliferation, with well-defined morphology ...
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