Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency

The availability of in vitro models of the human retina in which to perform pharmacological and toxicological studies is an urgent and unmet need. An essential step for developing in vitro models of human retina is the ability to generate laminated, physiologically functional and light-responsive re...

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Main Authors:	Dean Hallam, Gerrit Hilgen, Birthe Dorgau, Lili Zhu, Min Yu, Sanja Bojic, Philip Hewitt, Michael Schmitt, Marianne Uteng, Stefan Kustermann, David Steel, Mike Nicholds, Rob Thomas, Achim Treumann, Andrew Porter, Evelyne Sernagor, Lyle Armstrong, Majlinda Lako
Format:	Default Article
Published:	2018
Subjects:	Mechanical engineering not elsewhere classified untagged Mechanical Engineering not elsewhere classified
Online Access:	https://hdl.handle.net/2134/34320
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id	rr-article-9561170
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spelling	rr-article-95611702018-07-13T00:00:00Z Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency Dean Hallam (7211360) Gerrit Hilgen (128467) Birthe Dorgau (7211363) Lili Zhu (219363) Min Yu (120607) Sanja Bojic (1700833) Philip Hewitt (4665538) Michael Schmitt (17761) Marianne Uteng (53549) Stefan Kustermann (3070632) David Steel (87365) Mike Nicholds (7211366) Rob Thomas (1249266) Achim Treumann (263173) Andrew Porter (3767770) Evelyne Sernagor (1342965) Lyle Armstrong (3719758) Majlinda Lako (3719764) Mechanical engineering not elsewhere classified untagged Mechanical Engineering not elsewhere classified The availability of in vitro models of the human retina in which to perform pharmacological and toxicological studies is an urgent and unmet need. An essential step for developing in vitro models of human retina is the ability to generate laminated, physiologically functional and light-responsive retinal organoids from renewable and patient specific sources. We investigated five different human induced pluripotent stem cell (iPSC) lines and showed a significant variability in their efficiency to generate retinal organoids. Despite this variability, by month 5 of differentiation, all iPSC-derived retinal organoids were able to generate light responses, albeit immature, comparable to the earliest light responses recorded from the neonatal mouse retina, close to the period of eye opening. All iPSC-derived retinal organoids exhibited at this time a well-formed outer nuclear like layer containing photoreceptors with inner segments, connecting cilium and outer like segments. The differentiation process was highly dependent on seeding cell density and nutrient availability determined by factorial experimental design. We adopted the differentiation protocol to a multiwell plate format which enhanced generation of retinal organoids with retinal pigmented epithelium (RPE) and improved ganglion cell development and the response to physiological stimuli. We tested the response of iPSC-derived retinal organoids to Moxifloxacin and showed that similarly to in vivo adult mouse retina, the primary affected cell types were photoreceptors. Together our data indicate that light responsive retinal organoids derived from carefully selected and differentiation efficient iPSC lines can be generated at the scale needed for pharmacology and drug screening purposes. © AlphaMed Press 2018. 2018-07-13T00:00:00Z Text Journal contribution 2134/34320 https://figshare.com/articles/journal_contribution/Human_induced_pluripotent_stem_cells_generate_light_responsive_retinal_organoids_with_variable_and_nutrient_dependent_efficiency_/9561170 CC BY 4.0
institution	Loughborough University
collection	Figshare
topic	Mechanical engineering not elsewhere classified untagged Mechanical Engineering not elsewhere classified
spellingShingle	Mechanical engineering not elsewhere classified untagged Mechanical Engineering not elsewhere classified Dean Hallam Gerrit Hilgen Birthe Dorgau Lili Zhu Min Yu Sanja Bojic Philip Hewitt Michael Schmitt Marianne Uteng Stefan Kustermann David Steel Mike Nicholds Rob Thomas Achim Treumann Andrew Porter Evelyne Sernagor Lyle Armstrong Majlinda Lako Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency
description	The availability of in vitro models of the human retina in which to perform pharmacological and toxicological studies is an urgent and unmet need. An essential step for developing in vitro models of human retina is the ability to generate laminated, physiologically functional and light-responsive retinal organoids from renewable and patient specific sources. We investigated five different human induced pluripotent stem cell (iPSC) lines and showed a significant variability in their efficiency to generate retinal organoids. Despite this variability, by month 5 of differentiation, all iPSC-derived retinal organoids were able to generate light responses, albeit immature, comparable to the earliest light responses recorded from the neonatal mouse retina, close to the period of eye opening. All iPSC-derived retinal organoids exhibited at this time a well-formed outer nuclear like layer containing photoreceptors with inner segments, connecting cilium and outer like segments. The differentiation process was highly dependent on seeding cell density and nutrient availability determined by factorial experimental design. We adopted the differentiation protocol to a multiwell plate format which enhanced generation of retinal organoids with retinal pigmented epithelium (RPE) and improved ganglion cell development and the response to physiological stimuli. We tested the response of iPSC-derived retinal organoids to Moxifloxacin and showed that similarly to in vivo adult mouse retina, the primary affected cell types were photoreceptors. Together our data indicate that light responsive retinal organoids derived from carefully selected and differentiation efficient iPSC lines can be generated at the scale needed for pharmacology and drug screening purposes. © AlphaMed Press 2018.
format	Default Article
author	Dean Hallam Gerrit Hilgen Birthe Dorgau Lili Zhu Min Yu Sanja Bojic Philip Hewitt Michael Schmitt Marianne Uteng Stefan Kustermann David Steel Mike Nicholds Rob Thomas Achim Treumann Andrew Porter Evelyne Sernagor Lyle Armstrong Majlinda Lako
author_facet	Dean Hallam Gerrit Hilgen Birthe Dorgau Lili Zhu Min Yu Sanja Bojic Philip Hewitt Michael Schmitt Marianne Uteng Stefan Kustermann David Steel Mike Nicholds Rob Thomas Achim Treumann Andrew Porter Evelyne Sernagor Lyle Armstrong Majlinda Lako
author_sort	Dean Hallam (7211360)
title	Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency
title_short	Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency
title_full	Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency
title_fullStr	Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency
title_full_unstemmed	Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency
title_sort	human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency
publishDate	2018
url	https://hdl.handle.net/2134/34320
_version_	1797186870783770624

Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency

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