Graduate Student Pohang University of Science and Technology (POSTECH), Republic of Korea
Abstract: Cellular senescence of retinal pigment epithelium (RPE) cells plays a pivotal role in age-related visual decline, particularly in the progression of age-related macular degeneration (AMD). Yet, the molecular mechanisms underlying RPE senescence remain largely elusive. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to analyze RPE cells from young and aged mice, uncovering a strong association between dysregulated cell-matrix adhesion and RPE senescence. Using hydrogel-based models, we demonstrated that impaired integrin-mediated adhesion triggers a novel form of senescence, termed softness-induced senescence, in RPE cells. Mechanistically, a mechanically compliant microenvironment attenuates integrin signaling, leading to reduced activation of Yes-associated protein 1 (YAP), a pivotal mechanotransducer that maintains cellular homeostasis. Loss of YAP activity precipitates hallmark senescence phenotypes, including irreversible cell cycle arrest, upregulation of senescence-associated beta-galactosidase (SA-β-GAL), and increased secretion of senescence-associated secretory phenotype (SASP) factors. Notably, reactivation of YAP in senescent RPE cells reinstated stem cell-like transcriptional programs and reversed senescence-associated phenotypes. Furthermore, pharmacological activation of YAP using TRULI, a small-molecule YAP agonist, significantly improved visual function in both an AMD mouse model and physiologically aged mice. These findings establish the integrin-YAP mechanotransduction axis as a fundamental regulator of RPE senescence and highlight YAP activation as a promising therapeutic strategy for mitigating RPE aging and preserving visual function.
Funding Source: This work was supported by the National Research Foundation of Korea grant funded by the Korea government.
