Journal Article

Patient induced pluripotent stem cells identify specificities of a reticular pseudodrusen phenotype in age-related macular degeneration

Hewitt, Alex W., Krishna Sudhakar, Kavitha, Paull, Daniel, Liang, Helena H., Powell, Joseph E., Senabouth, Anne, Abbott, Carla J., Ansell, Brendan R. E., Lidgerwood, Grace E., Fletcher, Erica L., Nandrot, Emeline F., Mountford, Simon, Wu, Zhichao, Hall, Jenna C., Ma, Jessica YW, Bahlo, Melanie, Guymer, Robyn H., Mirzaei, Mehdi, Cazevieille, Chantal, Manes, Gaël, Kumar, Himeesh, Atkeson, Trevor, Thompson, Philip, Daniszewski, Maciej, Pébay, Alice, Barnett, Alexander, Hirokawa, Yumiko

2026

Overview

Background Age-related macular degeneration (AMD) is a leading cause of vision loss. Reticular pseudodrusen (RPD), deposits on the apical side of the retinal pigment epithelium (RPE), signify a distinctive and critical AMD phenotype. Yet, their molecular basis and relationship to the conventional drusen seen in AMD remain unclear. Methods We generated induced pluripotent stem cell-derived RPE cells from a clinically phenotyped cohort comprising only individuals with conventional drusen (AMD/RPD-) or with drusen coexisting with RPD (AMD/RPD +). To identify differences between the two cohorts, we performed single-cell transcriptomic, proteomic, quantitative trait locus (QTL) and transcriptome-wide association (TWAS) analyses, together with functional assays. Results AMD/RPD + RPE cells exhibited enrichment of extracellular matrix (ECM) and hypoxia-responsive pathways, and a relative underrepresentation of mitochondrial and oxidative phosphorylation processes, when compared with AMD/RPD- cells. Genetic analyses supported shared modulation of mitochondrial pathways across AMD, with additional regulatory signals associated with RPD risk. Functionally, all RPE cohorts formed drusen-like deposits in vitro. AMD/RPD- lines generated more basal deposits, whereas AMD/RPD + cells exhibited increased susceptibility to monolayer disruption. Conclusions These findings indicate that AMD with and without RPD represent mechanistically distinct entities and provide novel insight into the molecular mechanisms underlying disease heterogeneity in AMD.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Age-related macular degeneration / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer Research / Deposits / Epithelium / Ethylenediaminetetraacetic acid / Extracellular matrix / Fibroblasts / Genetic analysis / Genetic aspects / Genome regulation / Genomes / Genomics / Health risk assessment / Human Genetics / Human induced pluripotent stem cells / Hypoxia / Macular degeneration / Medicine/Public Health / Metabolomics / Microscopy / Molecular modelling / Oxidative phosphorylation / Penicillin / Phenotypes / Pluripotency / Proteomics / Quantitative genetics / Quantitative trait loci / Reticular pseudodrusen / Retinal pigment epithelium / Risk factors / RNA / RNA sequencing / Single-cell RNA sequencing / Stem cells / Systems Biology / Transcriptomes / Transcriptomics