功能失调的罕见CFH变体揭示了CFH在视网膜色素上皮细胞中的非经典作用。

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

作者信息

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

机构信息

Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.

Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, the Netherlands; Institute of Molecular and Clinical Ophthalmology, University of Basel, Basel, Switzerland.

出版信息

Stem Cell Reports. 2025 Jan 14;20(1):102385. doi: 10.1016/j.stemcr.2024.11.015. Epub 2025 Jan 2.

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.

补体因子H（CFH）常见基因变异与年龄相关性黄斑变性（AMD）有关。虽然之前大多数体外视网膜色素上皮（RPE）研究集中在常见的p.His402Tyr CFH变异上，但我们使用诱导多能干细胞衍生的视网膜色素上皮（iPSC-RPE）对在AMD中具有高外显率的罕见CFH变异进行了表征。我们的结果表明，在AMD RPE中检测到较低的因子H（FH）水平，这可能会破坏FH的经典和非经典作用。具体而言，与对照RPE相比，在N-视黄叉-N-视黄基乙醇胺（A2E）和蓝光刺激下，AMD RPE显示出更高的炎症率和一组差异表达基因减少。此外，在AMD RPE中观察到胆固醇流出和光感受器外段（POS）吞噬缺陷、补体水平失调、RPE下沉积物更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RPE功能中的新的非经典作用。