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

ABSTRACT: 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. We generated induced pluripotent stem cell-derived RPE cells from a clinically phenotyped cohort comprising only individuals with conventional drusen (AMD/RPD-) or drusen coexisting with RPD (AMD/RPD+). From these cells, we generated single-cell transcriptomics, proteomics, and functional data to identify differences between the two cohorts. We show that AMD/RPD+ RPE cells exhibit enrichment in extracellular matrix (ECM) remodelling, cytoskeletal, and hypoxia-responsive programs, whereas AMD/RPD- RPE cells display a relatively greater representation of mitochondrial and protein homeostasis pathways. Both subtypes demonstrated molecular hallmarks of ageing, including altered ECM regulation and mitochondrial decline, but differed in the direction and extent of pathway disruption. Expression and protein quantitative trait loci (QTLs) highlight shared genetic influences on mitochondrial and iron-handling pathways, while disease-interacting eQTLs and transcriptome-wide association study identify regulatory signals that are distinctive of the RPD subtype within AMD, including through regulation of ECM. Functionally, all iPSC-derived RPE formed drusen-like deposits in vitro: AMD/RPD- lines generated more basal deposits, whereas AMD/RPD+ cells exhibited greater structural instability under bisretinoid-induced stress. Together, 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pluripotent Stem Cell, Cell Culture

DISEASE(S): Age Related Macular Degeneration

SUBMITTER: Mehdi Mirzaei  

LAB HEAD: Alice Pebay

PROVIDER: PXD070797 | Pride | 2026-06-08

REPOSITORIES: Pride