Dalvi Sonal, Roll Michael, Chatterjee Amit, Kumar Lal Krishan, Bhogavalli Akshita, Foley Nathaniel, Arduino Cesar, Spencer Whitney, Reuben-Thomas Cheyenne, Ortolan Davide, Pébay Alice, Bharti Kapil, Anand-Apte Bela, Singh Ruchira
Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA.
Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institute of Health, Bethesda, MD, USA.
Dev Cell. 2024 Dec 16;59(24):3290-3305.e9. doi: 10.1016/j.devcel.2024.09.006. Epub 2024 Oct 2.
Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels. Therapeutically, RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in AMD/MD iPSC-RPE. Ultimately, this study defines a causal role of the MMP2-DAMP-RAGE-sPLA2-IIA axis in AMD/MDs.
年龄相关性黄斑变性（AMD）及相关黄斑营养不良（MDs）主要影响眼部的视网膜色素上皮（RPE）。玻璃膜疣是驱动AMD/MDs后期病变的一个标志。玻璃膜疣是富含脂质-蛋白质的RPE下细胞外沉积物，但玻璃膜疣如何形成和积累尚不清楚。我们利用来自AMD患者和三种不同MDs患者的人诱导多能干细胞（iPSC）衍生的RPE，以证明RPE分泌的基质金属蛋白酶2（MMP2）活性降低，通过损伤相关分子模式分子（DAMP）介导的晚期糖基化终产物受体（RAGE）激活和分泌型磷脂酶A2-IIA（sPLA2-IIA）水平升高，引发无菌性炎症并损害脂质稳态，从而以不依赖基因型的方式导致多种黄斑病变中的玻璃膜疣形成。在治疗方面，RPE特异性MMP2补充、RAGE拮抗肽和sPLA2-IIA小分子抑制剂改善了AMD/MD iPSC-RPE中玻璃膜疣的积累。最终，本研究确定了MMP2-DAMP-RAGE-sPLA2-IIA轴在AMD/MDs中的因果作用。
