用异源诱导多能干细胞模拟脉络膜血症。

Stem cells and development Pub Date : 2024-10-01 Epub Date: 2024-08-16 DOI:10.1089/scd.2024.0105
Ana Fragoso Fonseca, Rita Coelho, Mafalda Lopes- da-Silva, Luísa Lemos, Michael J Hall, Daniela Oliveira, Ana Sofia Falcão, Sandra Tenreiro, Miguel C Seabra, Pedro Antas
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引用次数: 0

摘要

脉络膜视网膜营养不良症(Choroideremia,CHM)是一种罕见的 X 连锁脉络膜视网膜营养不良症,由于 CHM 基因突变导致 Rab 护送蛋白 1(REP1)功能丧失,从而引起进行性视力丧失。CHM 病的特征是脉络膜、视网膜色素上皮(RPE)和视网膜的进行性变性。视网膜色素上皮(RPE)是单层的极化细胞,它支持光感受器,提供营养、生长因子和离子,并清除视网膜代谢废物,在CHM发病机制中起着核心作用。常用的模型(如 ARPE-19 细胞)不能准确再现 RPE 细胞的性质。人类诱导多能干细胞(hiPSC)可分化为 RPE 细胞(hiPSC-RPE),模拟原生 RPE 的主要特征,更适合研究视网膜疾病。因此,我们利用 hiPSC 的优势,建立了新的基于人类的 CHM 模型。我们通过 CRISPR/Cas9 生成了两个同源的 hiPSC 株系:一个是来自健康供体的 CHM 基因敲除株系,另一个是采用基因敲入方法的 CHM 患者矫正株系。分化后的 hiPSC-RPE 株系表现出原生 RPE 的关键形态学和生理学特征,包括存在紧密连接标记 Claudin-19 和 Zonula Occludens-1、吞噬感光体外节段、色素沉着、后有丝分裂状态以及特征性的多边形形状。此外,所有研究细胞都能形成视网膜器官组织。这项工作的结果是建立了同源的 hiPSC 株系,代表了一种新的、重要的 CHM 细胞模型。据我们所知,这是首次开发出用于模拟 CHM 疾病的同源细胞系,为研究 RPE 退化的发病机制提供了宝贵的工具。
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Modeling Choroideremia Disease with Isogenic Induced Pluripotent Stem Cells.

Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy causing progressive vision loss due to mutations in the CHM gene, leading to Rab escort protein 1 loss of function. CHM disease is characterized by a progressive degeneration of the choroid, the retinal pigment epithelium (RPE), and the retina. The RPE is a monolayer of polarized cells that supports photoreceptors, providing nutrients, growth factors, and ions, and removes retinal metabolism waste products, having a central role in CHM pathogenesis. Commonly used models such as ARPE-19 cells do not reproduce accurately the nature of RPE cells. Human induced pluripotent stem cells (hiPSCs) can be differentiated into RPE cells (hiPSC-RPE), which mimic key features of native RPE, being more suited to study retinal diseases. Therefore, we took advantage of hiPSCs to generate new human-based CHM models. Two isogenic hiPSC lines were generated through CRISPR/Cas9: a CHM knock-out line from a healthy donor and a corrected CHM patient line using a knock-in approach. The differentiated hiPSC-RPE lines exhibited critical morphological and physiological characteristics of native RPE, including the presence of the tight junction markers Claudin-19 and Zonula Occludens-1, phagocytosis of photoreceptor outer segments, pigmentation, a postmitotic state, and the characteristic polygonal shape. In addition, all the studied cells were able to form retinal organoids. This work resulted in the establishment of isogenic hiPSC lines, representing a new and important CHM cellular model. To our knowledge, this is the first time that isogenic cell lines have been developed to model CHM disease, providing a valuable tool for studying the mechanisms at the onset of RPE degeneration.

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