Human Retinal Organoids Provide a Suitable Tool for Toxicological Investigations: A Comprehensive Validation Using Drugs and Compounds Affecting the Retina.
Human Retinal Organoids Provide a Suitable Tool for Toxicological Investigations: A Comprehensive Validation Using Drugs and Compounds Affecting the Retina.
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DOI：
10.1093/stcltm/szab010
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发表时间：
2022-03-17
影响因子：
6
通讯作者：
Lako M
中科院分区：
文献类型：
--
作者：
Dorgau B;Georgiou M;Chaudhary A;Moya-Molina M;Collin J;Queen R;Hilgen G;Davey T;Hewitt P;Schmitt M;Kustermann S;Pognan F;Steel DH;Sernagor E;Armstrong L;Lako M
视网膜药物毒性筛查对于许多疾病的安全治疗策略的发展至关重要。为此，来源于人多能干细胞（hPSC）的视网膜类器官提供了合适的筛选平台，因为它们与人视网膜相似并且易于大规模生成。在这项研究中，两种hPSC细胞系分化为视网膜类器官，其包含多个核和突触层中的所有关键视网膜细胞类型。视网膜类器官的单细胞RNA-Seq表明视网膜神经节细胞的维持和双极细胞的发育：两种细胞类型分离成几种亚型。选择酮咯酸、地高辛、硫利达嗪、西地那非、乙醇和甲醇作为筛选视网膜类器官的关键化合物，因为文献中描述了其众所周知的视网膜毒性特征。hPSC衍生的视网膜类器官暴露于地高辛、硫利达嗪和西地那非导致感光细胞死亡，而地高辛和硫利达嗪还影响所有其他细胞类型，包括Müller神经胶质细胞。所有药物治疗均引起星形胶质细胞活化，表现为树突出芽进入神经上皮。尽管药物暴露后反应性视网膜神经节细胞的数量减少，但类器官对光的反应能力得到了保留。这些数据表明，类器官中的药物作用与体内模型和/或人体中报告的药物作用相似，从而为其适用于毒理学研究提供了第一个可靠的实验证据。
Retinal drug toxicity screening is essential for the development of safe treatment strategies for a large number of diseases. To this end, retinal organoids derived from human pluripotent stem cells (hPSCs) provide a suitable screening platform due to their similarity to the human retina and the ease of generation in large-scale formats. In this study, two hPSC cell lines were differentiated to retinal organoids, which comprised all key retinal cell types in multiple nuclear and synaptic layers. Single-cell RNA-Seq of retinal organoids indicated the maintenance of retinal ganglion cells and development of bipolar cells: both cell types segregated into several subtypes. Ketorolac, digoxin, thioridazine, sildenafil, ethanol, and methanol were selected as key compounds to screen on retinal organoids because of their well-known retinal toxicity profile described in the literature. Exposure of the hPSC-derived retinal organoids to digoxin, thioridazine, and sildenafil resulted in photoreceptor cell death, while digoxin and thioridazine additionally affected all other cell types, including Müller glia cells. All drug treatments caused activation of astrocytes, indicated by dendrites sprouting into neuroepithelium. The ability to respond to light was preserved in organoids although the number of responsive retinal ganglion cells decreased after drug exposure. These data indicate similar drug effects in organoids to those reported in in vivo models and/or in humans, thus providing the first robust experimental evidence of their suitability for toxicological studies.
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DOI：
10.1016/j.bbagen.2015.05.023
发表时间：
2016-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Dulle JE;Fort PE
通讯作者：
Fort PE
影响因子：
5.3
作者：
Fernández-Sánchez L;Lax P;Campello L;Pinilla I;Cuenca N
通讯作者：
Cuenca N
人类诱导的多能干细胞产生具有可变和养分依赖性效率的光响应性视网膜器官。
DOI：
10.1002/stem.2883
发表时间：
2018-10
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
Hallam D;Hilgen G;Dorgau B;Zhu L;Yu M;Bojic S;Hewitt P;Schmitt M;Uteng M;Kustermann S;Steel D;Nicholds M;Thomas R;Treumann A;Porter A;Sernagor E;Armstrong L;Lako M
通讯作者：
Lako M
影响因子：
14
作者：
Dorgau, Birthe;Felemban, Majed;Lako, Majlinda
通讯作者：
Lako, Majlinda
影响因子：
64.5
作者：
Cowan CS;Renner M;De Gennaro M;Gross-Scherf B;Goldblum D;Hou Y;Munz M;Rodrigues TM;Krol J;Szikra T;Cuttat R;Waldt A;Papasaikas P;Diggelmann R;Patino-Alvarez CP;Galliker P;Spirig SE;Pavlinic D;Gerber-Hollbach N;Schuierer S;Srdanovic A;Balogh M;Panero R;Kusnyerik A;Szabo A;Stadler MB;Orgül S;Picelli S;Hasler PW;Hierlemann A;Scholl HPN;Roma G;Nigsch F;Roska B
通讯作者：
Roska B