Non-canonical roles of CFH in retinal pigment epithelial cells revealed by dysfunctional rare CFH variants.

IF 5.9 2区医学 Q1 CELL & TISSUE ENGINEERING

Stem Cell Reports Pub Date : 2025-01-14 Epub Date: 2025-01-02 DOI:10.1016/j.stemcr.2024.11.015

Sofie C A Brink, Louet Koolen, Caroline C W Klaver, Remko A Bakker, Anneke I den Hollander, Seba Almedawar

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Abstract

Complement factor H (CFH) common genetic variants have been associated with age-related macular degeneration (AMD). While most previous in vitro RPE studies focused on the common p.His402Tyr CFH variant, we characterized rare CFH variants that are highly penetrant for AMD using induced pluripotent stem-cell-derived retinal pigment epithelium (iPSC-RPE). Our results show that lower factor H (FH) levels are detected in AMD RPE, which potentially disrupt canonical and non-canonical roles of FH. Specifically, AMD RPE displays higher inflammation rate and a reduced set of differentially expressed genes compared to control RPE upon N-retinylidene-N-retinylethanolamine (A2E) and blue light challenge. Additionally, cholesterol efflux and photoreceptor outer segment (POS) phagocytosis defects, dysregulated complement levels, larger sub-RPE deposits, and increased mitochondrial stress were observed in AMD RPE. Thus, our study reveals new non-canonical roles for FH in regulating important RPE functions.

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功能失调的罕见CFH变异揭示了CFH在视网膜色素上皮细胞中的非规范作用。

补体因子H （CFH）常见的遗传变异与年龄相关性黄斑变性（AMD）有关。虽然之前的大多数体外RPE研究都集中在常见的p.His402Tyr CFH变异上，但我们使用诱导多能干细胞来源的视网膜色素上皮（iPSC-RPE）表征了罕见的CFH变异，这些CFH变异对AMD具有高渗透性。我们的研究结果表明，在AMD RPE中检测到较低的因子H （FH）水平，这可能会破坏FH的规范和非规范作用。具体来说，AMD RPE在n -视黄醛- n -视黄醛乙醇胺（A2E）和蓝光刺激下表现出更高的炎症率和一组减少的差异表达基因。此外，在AMD RPE中观察到胆固醇外排和光感受器外段（POS）吞噬缺陷、补体水平失调、亚RPE沉积较大以及线粒体应激增加。因此，我们的研究揭示了FH在调节重要的RPE功能中的新的非规范作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Stem Cell Reports CELL & TISSUE ENGINEERING-CELL BIOLOGY

CiteScore

10.50

自引率

1.70%

发文量

200

审稿时长

28 weeks

期刊介绍： Stem Cell Reports publishes high-quality, peer-reviewed research presenting conceptual or practical advances across the breadth of stem cell research and its applications to medicine. Our particular focus on shorter, single-point articles, timely publication, strong editorial decision-making and scientific input by leaders in the field and a "scoop protection" mechanism are reasons to submit your best papers.