Cells of the human retinal pigment epithelium (RPE) have a regular epithelial cell shape within the tissue in situ, but for reasons that remain elusive the RPE shows an incomplete and variable ability to re-develop an epithelial phenotype after propagation in vitro. In other epithelial cell cultures, formation of an adherens junction (AJ) composed of E-cadherin plays an important early inductive role in epithelial morphogenesis, but E-cadherin is largely absent from the RPE. In this review, the contribution of cadherins, both minor (E-cadherin) and major (N-cadherin), to RPE phenotype development is discussed. Emphasis is placed on the importance for future studies of actin cytoskeletal remodeling during assembly of the AJ, which in epithelial cells results in an actin organization that is characteristically zonular. Other markers of RPE phenotype that are used to gauge the maturation state of RPE cultures including tissue-specific protein expression, protein polarity, and pigmentation are described. An argument is made that RPE epithelial phenotype, cadherin-based cell-cell adhesion and melanization are linked by a common signaling pathway: the Wnt/beta-catenin pathway. Analyzing this pathway and its intersecting signaling networks is suggested as a useful framework for dissecting the steps in RPE morphogenesis. Also discussed is the effect of aging on RPE phenotype. Preliminary evidence is provided to suggest that light-induced sub-lethal oxidative stress to cultured ARPE-19 cells impairs organelle motility. Organelle translocation, which is mediated by stress-susceptible cytoskeletal scaffolds, is an essential process in cell phenotype development and retention. The observation of impaired organelle motility therefore raises the possibility that low levels of stress, which are believed to accompany RPE aging, may produce subtle disruptions of cell phenotype. Over time these would be expected to diminish the support functions performed by the RPE on behalf of photoreceptors, theoretically contributing to aging retinal disease such as age-related macular degeneration (AMD). Analyzing sub-lethal stress that produces declines in RPE functional efficiency rather than overt cell death is suggested as a useful future direction for understanding the effects of age on RPE organization and physiology. As for phenotype and pigmentation, a role for the Wnt/beta-catenin pathway is also suggested in regulating the RPE response to oxidative stress. Exploration of this pathway in the RPE therefore may provide a unifying strategy for advancing our understanding of both RPE phenotype and the consequences of mild oxidative stress on RPE structure and function.

中文翻译：

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上皮表型和 RPE：答案是否在 Wnt 中？

人视网膜色素上皮 (RPE) 的细胞在原位组织内具有规则的上皮细胞形状，但由于仍然难以捉摸的原因，RPE 显示出在体外繁殖后重新形成上皮表型的不完整和可变能力。在其他上皮细胞培养物中，由 E-钙粘蛋白组成的粘附连接 (AJ) 的形成在上皮形态发生中起着重要的早期诱导作用，但 RPE 中基本上不存在 E-钙粘蛋白。在这篇综述中，讨论了次要 (E-钙粘蛋白) 和主要 (N-钙粘蛋白) 钙粘蛋白对 RPE 表型发展的贡献。重点放在未来研究 AJ 组装过程中肌动蛋白细胞骨架重塑的重要性上，这在上皮细胞中会导致肌动蛋白组织具有典型的带状结构。描述了用于衡量 RPE 培养物成熟状态的 RPE 表型的其他标记，包括组织特异性蛋白质表达、蛋白质极性和色素沉着。有一种观点认为，RPE 上皮表型、基于钙粘蛋白的细胞-细胞粘附和黑化与一条共同的信号通路有关：Wnt/β-连环蛋白通路。分析这条通路及其交叉的信号网络被认为是剖析 RPE 形态发生步骤的有用框架。还讨论了衰老对 RPE 表型的影响。初步证据表明，光诱导的亚致死氧化应激对培养的 ARPE-19 细胞会损害细胞器运动。细胞器易位，由易受应激的细胞骨架支架介导，是细胞表型发展和保留的重要过程。因此，对细胞器运动受损的观察提出了一种可能性，即据信伴随 RPE 老化的低水平压力可能会导致细胞表型的细微破坏。随着时间的推移，这些预计会减少 RPE 代表光感受器执行的支持功能，理论上会导致老化的视网膜疾病，如年龄相关性黄斑变性 (AMD)。分析导致 RPE 功能效率下降而不是明显细胞死亡的亚致死压力被认为是了解年龄对 RPE 组织和生理影响的有用未来方向。至于表型和色素沉着，还建议 Wnt/β-连环蛋白途径在调节 RPE 对氧化应激的反应中发挥作用。