Retinal organoids provide unique insights into molecular signatures of inherited retinal disease throughout retinogenesis.
Retinal organoids provide unique insights into molecular signatures of inherited retinal disease throughout retinogenesis.
复制标题
视网膜器官在整个视网膜生成过程中对遗传性视网膜疾病的分子特征提供了独特的见解。
DOI：
10.1111/joa.13768
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发表时间：
2023-08
影响因子：
2.4
通讯作者：
Lako, Majlinda
中科院分区：
文献类型：
--
作者：
Watson, Avril;Lako, Majlinda
关键词：
在过去的十年中，对诱导多能干细胞（iPSC）衍生的视网膜类器官和视网膜色素上皮（RPE）模型的需求显着增加，用于遗传性视网膜病变的建模。这些模型与胎儿视网膜相当，直到视网膜发生的后期，表达视网膜功能所需的所有关键神经元标记物。这些模型已被证明在理解视网膜发生方面是非常宝贵的，特别是在患者特异性疾病的背景下。遗传性视网膜病被描述为临床和表型异质性，因此在每种视网膜疾病的情况下开发基因/突变特异性动物模型在经济上或伦理上都不可行。此外，由于解剖学差异和未能重现人类疾病表型，许多动物模型在疾病发病机制的研究中是不够的。相比之下，iPSC衍生的视网膜模型提供了一个高通量平台，这与研究人类健康和疾病在生理上相关。它们还可作为药物筛选、基因治疗方法和临床前研究中新疗法的体外毒理学的平台。干细胞衍生的视网膜模型的一个独特特征是能够模拟体内视网膜发生，以高度可及的方式提供对发育中视网膜细胞中致病突变影响的无与伦比的见解。本文旨在在几种遗传性视网膜病（包括色素性视网膜炎、Stargardt病和视网膜母细胞瘤）的疾病建模背景下，向读者概述iPSC衍生的视网膜类器官和/或RPE。我们描述了每个模型的能力，概括在体内疾病表型，验证以前的研究结果，从动物模型和识别新的病理机制，支持个人IRD。近年来，视网膜类器官已成为理解视网膜发生的非常有用的工具，特别是在视网膜疾病的背景下。多能干细胞（PSC）可以直接来源于受影响患者的体细胞，或者，现有的多能细胞系可以进行基因编辑以携带感兴趣的突变。然后，这些PSC可以在体外定向分化为视网膜组织，特别是视网膜类器官和视网膜色素上皮（RPE），为研究者提供大量的疾病相关组织进行分析。在科学研究中使用视网膜类器官和RPE有几种应用，包括疾病建模，了解视网膜发生，药物筛选和毒理学筛选。这篇综述的目的是作为一个引物的实用性视网膜类器官和RPE，来自PSC，在遗传性视网膜病变的研究。利用视网膜色素变性、Stargardt病和视网膜母细胞瘤等视网膜疾病，我们讨论了PSC衍生的视网膜组织如何证实动物模型的结果，并发现疾病的新分子特征，这些特征可能对于开发针对遗传性失明的疗法至关重要。
The demand for induced pluripotent stem cells (iPSC)‐derived retinal organoid and retinal pigment epithelium (RPE) models for the modelling of inherited retinopathies has increased significantly in the last decade. These models are comparable with foetal retinas up until the later stages of retinogenesis, expressing all of the key neuronal markers necessary for retinal function. These models have proven to be invaluable in the understanding of retinogenesis, particular in the context of patient‐specific diseases. Inherited retinopathies are infamously described as clinically and phenotypically heterogeneous, such that developing gene/mutation‐specific animal models in each instance of retinal disease is not financially or ethically feasible. Further to this, many animal models are insufficient in the study of disease pathogenesis due to anatomical differences and failure to recapitulate human disease phenotypes. In contrast, iPSC‐derived retinal models provide a high throughput platform which is physiologically relevant for studying human health and disease. They also serve as a platform for drug screening, gene therapy approaches and in vitro toxicology of novel therapeutics in pre‐clinical studies. One unique characteristic of stem cell‐derived retinal models is the ability to mimic in vivo retinogenesis, providing unparalleled insights into the effects of pathogenic mutations in cells of the developing retina, in a highly accessible way. This review aims to give the reader an overview of iPSC‐derived retinal organoids and/or RPE in the context of disease modelling of several inherited retinopathies including Retinitis Pigmentosa, Stargardt disease and Retinoblastoma. We describe the ability of each model to recapitulate in vivo disease phenotypes, validate previous findings from animal models and identify novel pathomechanisms that underpin individual IRDs. Retinal organoids have become an exceedingly useful tool in recent years for understanding retinogenesis, particularly in the context of retinal disease. Pluripotent stem cells (PSCs) can be derived directly from somatic cells of affected patients, or alternatively, existing pluripotent lines can undergo gene editing to harbour mutations of interest. These PSCs can then undertake a directed differentiation to retinal tissues in vitro, specifically retinal organoids and retinal pigment epithelium (RPE), giving the investigator an abundance of disease‐relevant tissue to assay. There are several applications for the use of retinal organoids and RPE in the scientific study including disease modelling, understanding retinogenesis, drug screening and toxicological screening. This review aims to serve as a primer in the utility of retinal organoids and RPE, derived from PSCs, in the study of inherited retinopathies. Using retinal diseases, such as Retinitis pigmentosa, Stargardt disease and Retinoblastoma, we discuss how PSC‐derived retinal tissues can corroborate results from animal models and uncover novel molecular signatures of disease that may be crucial in developing therapies against inherited blindness.
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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
影响因子：
3.9
作者：
Bax, Nathalie M.;Sangermano, Riccardo;Cremers, Frans P. M.
通讯作者：
Cremers, Frans P. M.
影响因子：
168.9
作者：
Dimaras, Helen;Kimani, Kahaki;Gallie, Brenda L.
通讯作者：
Gallie, Brenda L.
影响因子：
3.5
作者：
Comitato, Antonella;Spampanato, Carmine;Marigo, Valeria
通讯作者：
Marigo, Valeria