Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies

IF 10.7 1区生物学 Q1 CELL BIOLOGY

Developmental cell Pub Date : 2024-10-02 DOI:10.1016/j.devcel.2024.09.006

Sonal Dalvi, Michael Roll, Amit Chatterjee, Lal Krishan Kumar, Akshita Bhogavalli, Nathaniel Foley, Cesar Arduino, Whitney Spencer, Cheyenne Reuben-Thomas, Davide Ortolan, Alice Pébay, Kapil Bharti, Bela Anand-Apte, Ruchira Singh

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Abstract

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.

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基于人类 iPSC 的疾病建模研究发现了一种常见的机理缺陷，以及治疗老年性黄斑变性和相关黄斑营养不良症的潜在疗法

老年性黄斑变性（AMD）和相关的黄斑营养不良症（MDs）主要影响眼睛中的视网膜色素上皮（RPE）。黄斑变性/黄斑萎缩症的一个特征是色素沉着，它是后期病变的驱动因素。色素沉着是RPE下富含脂质蛋白的细胞外沉积物，但色素沉着是如何形成和积累的尚不清楚。我们利用诱导多能干细胞（iPSC）从 AMD 患者和三种不同的多发性黄斑病变中提取的 RPE，证明 RPE 分泌的基质金属蛋白酶 2（MMP2）活性降低是多种黄斑病变形成葡萄色素的原因之一。通过损伤相关分子模式分子（DAMP）介导的高级糖化终产物受体（RAGE）激活和分泌型磷脂酶 2-IIA（sPLA2-IIA）水平升高，引发无菌性炎症和脂质稳态受损。在治疗上，RPE 特异性 MMP2 补充剂、RAGE 拮抗肽和 sPLA2-IIA 小分子抑制剂可改善 AMD/MD iPSC-RPE 的色素累积。最终，这项研究确定了 MMP2-DAMP-RAGE-sPLA2-IIA 轴在 AMD/MD 中的因果作用。

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来源期刊

Developmental cell 生物-发育生物学

CiteScore

18.90

自引率

1.70%

发文量

203

审稿时长

3-6 weeks

期刊介绍： Developmental Cell, established in 2001, is a comprehensive journal that explores a wide range of topics in cell and developmental biology. Our publication encompasses work across various disciplines within biology, with a particular emphasis on investigating the intersections between cell biology, developmental biology, and other related fields. Our primary objective is to present research conducted through a cell biological perspective, addressing the essential mechanisms governing cell function, cellular interactions, and responses to the environment. Moreover, we focus on understanding the collective behavior of cells, culminating in the formation of tissues, organs, and whole organisms, while also investigating the consequences of any malfunctions in these intricate processes.