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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月10日

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

摘要

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.