Ocular and Stem Cell Translational Research Section, National Eye Institute, NIH, Bethesda, MD, USA.
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands; AbbVie, Genomics Research Center, Cambridge, MA, USA.
Exp Eye Res. 2022 Sep;222:109170. doi: 10.1016/j.exer.2022.109170. Epub 2022 Jul 11.
Age-related macular degeneration (AMD) is a disease that affects the macula - the central part of the retina. It is a leading cause of irreversible vision loss in the elderly. AMD onset is marked by the presence of lipid- and protein-rich extracellular deposits beneath the retinal pigment epithelium (RPE), a monolayer of polarized, pigmented epithelial cells located between the photoreceptors and the choroidal blood supply. Progression of AMD to the late nonexudative "dry" stage of AMD, also called geographic atrophy, is linked to progressive loss of areas of the RPE, photoreceptors, and underlying choriocapillaris leading to a severe decline in patients' vision. Differential susceptibility of macular RPE in AMD and the lack of an anatomical macula in most lab animal models has promoted the use of in vitro models of the RPE. In addition, the need for high throughput platforms to test potential therapies has driven the creation and characterization of in vitro model systems that recapitulate morphologic and functional abnormalities associated with human AMD. These models range from spontaneously formed cell line ARPE19, immortalized cell lines such as hTERT-RPE1, RPE-J, and D407, to primary human (fetal or adult) or animal (mouse and pig) RPE cells, and embryonic and induced pluripotent stem cell (iPSC) derived RPE. Hallmark RPE phenotypes, such as cobblestone morphology, pigmentation, and polarization, vary significantly betweendifferent models and culture conditions used in different labs, which would directly impact their usability for investigating different aspects of AMD biology. Here the AMD Disease Models task group of the Ryan Initiative for Macular Research (RIMR) provides a summary of several currently used in vitro RPE models, historical aspects of their development, RPE phenotypes that are attainable in these models, their ability to model different aspects of AMD pathophysiology, and pros/cons for their use in the RPE and AMD fields. In addition, due to the burgeoning use of iPSC derived RPE cells, the critical need for developing standards for differentiating and rigorously characterizing RPE cell appearance, morphology, and function are discussed.
年龄相关性黄斑变性（AMD）是一种影响视网膜黄斑的疾病。它是老年人不可逆转视力丧失的主要原因。AMD 的发病以视网膜色素上皮（RPE）下富含脂质和蛋白质的细胞外沉积物的存在为标志，RPE 是位于光感受器和脉络膜血液供应之间的单层极化色素上皮细胞。AMD 进展为晚期非渗出性“干性”AMD 阶段，也称为地图状萎缩，与 RPE、光感受器和下方脉络膜毛细血管的进行性丧失有关，导致患者视力严重下降。AMD 中黄斑 RPE 的差异易感性以及大多数实验室动物模型中缺乏解剖学上的黄斑，促进了 RPE 的体外模型的使用。此外，需要高通量平台来测试潜在的治疗方法，这推动了体外模型系统的创建和表征，这些系统再现了与人类 AMD 相关的形态和功能异常。这些模型范围从自发形成的细胞系 ARPE19、永生化细胞系（如 hTERT-RPE1、RPE-J 和 D407）到原代人（胎儿或成人）或动物（小鼠和猪）RPE 细胞，以及胚胎和诱导多能干细胞（iPSC）衍生的 RPE。不同模型之间的 RPE 表型差异很大，例如鹅卵石形态、色素沉着和极化，以及不同实验室使用的不同培养条件，这将直接影响它们用于研究 AMD 生物学不同方面的可用性。在这里，Ryan 黄斑研究倡议（RIMR）的 AMD 疾病模型工作组提供了几种目前使用的体外 RPE 模型的总结，包括它们的历史发展、在这些模型中可达到的 RPE 表型、它们模拟 AMD 病理生理学不同方面的能力，以及它们在 RPE 和 AMD 领域的使用的优缺点。此外，由于 iPSC 衍生的 RPE 细胞的使用日益增多，迫切需要开发用于分化和严格表征 RPE 细胞外观、形态和功能的标准。
