Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness.
Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness.
复制标题
DOI：
10.3389/fncel.2020.00179
复制
发表时间：
2020
影响因子：
5.3
通讯作者：
Nasonkin IO
中科院分区：
文献类型：
--
作者：
Singh RK;Nasonkin IO
从多能干细胞自我形成视网膜组织为开发视网膜退行性疾病的新疗法带来了巨大的希望，而这在以前似乎是无法实现的。随着诱导多能干细胞或/和基于CRISPR的重组工程的使用，视网膜器质技术为建立人类视网膜退行性疾病模型提供了一条途径，用于研究病理，描述机制，并建立大规模药物筛选的平台。与此同时，与发育中的人类胚胎视网膜组织非常相似的视网膜类器官被视为多潜能视网膜前体细胞、年轻的光感受器和整个视网膜组织的来源，这些组织可能会被移植到视网膜下间隙，目的是用新的视网膜“补丁”取代患者退化的视网膜。这两种方法(移植和建模/药物筛选)都是在佐井佳树展示了从多能干细胞获得哺乳动物视网膜组织的可行性时提出的，并引起了许多兴奋。随着这两种方法在体外和体内的进一步研究和测试，一个主要的隐含限制很快就变得明显起来：缺乏视网膜色素上皮(RPE)细胞的统一层，这通常存在于哺乳动物的视网膜中，包围着光感受器层，首先发育和成熟。在发育过程中，RPE层极化为顶端和基端，并在顶端建立微绒毛，与光感受器相互作用，滋养光感受器外节，并通过将11-跨视网膜(漂白的色素)循环回到11-顺式视网膜而参与视觉周期。然而，视网膜有机体要么没有RPE层，要么主要在一侧携带片状RPE，从而将发育中的有机体中的大多数光感受器直接暴露在神经介质中。视网膜顶端RPE和光感受器之间的关键生态位的重建是许多视网膜疾病机制的起源，到目前为止还无法实现，这对建模/药物筛选和移植方法都造成了明显的限制，也是许多实验室研究的重点。在这里，我们解剖不同的视网膜退行性疾病，并分析视网膜器质技术如何以及在哪里对开发治疗做出最大贡献，即使在目前的限制和缺乏由RPE支持的长而有功能的外部节段的情况下。
The self-formation of retinal tissue from pluripotent stem cells generated a tremendous promise for developing new therapies of retinal degenerative diseases, which previously seemed unattainable. Together with use of induced pluripotent stem cells or/and CRISPR-based recombineering the retinal organoid technology provided an avenue for developing models of human retinal degenerative diseases “in a dish” for studying the pathology, delineating the mechanisms and also establishing a platform for large-scale drug screening. At the same time, retinal organoids, highly resembling developing human fetal retinal tissue, are viewed as source of multipotential retinal progenitors, young photoreceptors and just the whole retinal tissue, which may be transplanted into the subretinal space with a goal of replacing patient’s degenerated retina with a new retinal “patch.” Both approaches (transplantation and modeling/drug screening) were projected when Yoshiki Sasai demonstrated the feasibility of deriving mammalian retinal tissue from pluripotent stem cells, and generated a lot of excitement. With further work and testing of both approaches in vitro and in vivo, a major implicit limitation has become apparent pretty quickly: the absence of the uniform layer of Retinal Pigment Epithelium (RPE) cells, which is normally present in mammalian retina, surrounds photoreceptor layer and develops and matures first. The RPE layer polarize into apical and basal sides during development and establish microvilli on the apical side, interacting with photoreceptors, nurturing photoreceptor outer segments and participating in the visual cycle by recycling 11-trans retinal (bleached pigment) back to 11-cis retinal. Retinal organoids, however, either do not have RPE layer or carry patches of RPE mostly on one side, thus directly exposing most photoreceptors in the developing organoids to neural medium. Recreation of the critical retinal niche between the apical RPE and photoreceptors, where many retinal disease mechanisms originate, is so far unattainable, imposes clear limitations on both modeling/drug screening and transplantation approaches and is a focus of investigation in many labs. Here we dissect different retinal degenerative diseases and analyze how and where retinal organoid technology can contribute the most to developing therapies even with a current limitation and absence of long and functional outer segments, supported by RPE.
登录
查看更多内容
影响因子：
5.2
作者：
Capowski, Elizabeth E.;Wright, Lynda S.;Liang, Kun;Phillips, M. Joseph;Wallace, Kyle;Petelinsek, Anna;Hagstrom, Anna;Pinilla, Isabel;Borys, Katarzyna;Lien, Jessica;Min, Jee Hong;Keles, Sunduz;Thomson, James A.;Gamm, David M.
通讯作者：
Gamm, David M.
影响因子：
5.9
作者：
Assawachananont, Juthaporn;Mandai, Michiko;Okamoto, Satoshi;Yamada, Chikako;Eiraku, Mototsugu;Yonemura, Shigenobu;Sasai, Yoshiki;Takahashi, Masayo
通讯作者：
Takahashi, Masayo
影响因子：
5.9
作者：
Brooks, Matthew J.;Chen, Holly Y.;Swaroop, Anand
通讯作者：
Swaroop, Anand
影响因子：
4.5
作者：
Bharti K;Gasper M;Ou J;Brucato M;Clore-Gronenborn K;Pickel J;Arnheiter H
通讯作者：
Arnheiter H
影响因子：
2.7
作者：
Burnett JB;Lupu FI;Eggenschwiler JT
通讯作者：
Eggenschwiler JT