New study highlights the sensitivity of hiPSC-RPE cells for investigating retinal disease mechanisms
Researchers at Experimentica have demonstrated that human induced pluripotent stem cell-derived retinal pigment epithelium (hiPSC-RPE) cells provide a highly relevant in vitro model for studying oxidative stress-related retinal diseases, including age-related macular degeneration (AMD). The study showed that these cells closely resemble native human RPE tissue both morphologically and functionally, making them a valuable platform for preclinical research and drug development.
Oxidative stress-induced gene expression changes in hiPSC-RPE cells
A key focus of the study was to characterize gene expression changes triggered by oxidative stress. Using sodium iodate (NaIO3), a well-established RPE-specific stress inducer, researchers identified a distinct molecular response in hiPSC-RPE cells. The hiPSC-RPE model revealed robust oxidative stress-induced changes in gene expression, characterized by upregulation of VEGFA, HIF1A, TXN, CHAC1, and SLC7A11 and downregulation of TXNIP. Together, these findings demonstrate activation of pro-angiogenic and ferroptosis-associated pathways, highlighting the model’s suitability for studying retinal disease mechanisms and therapeutic targets.
ROS levels increased significantly before viability loss was observed
Notably, the hiPSC-RPE model detected substantial increases in reactive oxygen species (ROS) at low stress levels before any measurable loss of cell viability occurred. This sensitivity enables the identification of early molecular events preceding cell damage, providing a powerful tool for evaluating novel therapeutic interventions.
Activation of the thioredoxin system and ferroptosis-related gene expression
The study also demonstrated activation of the thioredoxin antioxidant system, which plays a central role in maintaining cellular redox balance. Increased TXN expression together with reduced TXNIP expression suggests that hiPSC-RPE cells mount a protective response against oxidative injury. At the same time, elevated VEGFA and HIF1A expression mirrors pathways implicated in pathological angiogenesis observed in wet age-related macular degeneration (AMD).
Importantly, the hiPSC-RPE model captured gene expression signatures linked to ferroptosis, a form of iron-dependent cell death increasingly associated with retinal degeneration. Upregulation of CHAC1 and SLC7A11 highlights the balance between cellular adaptation and pro-ferroptotic stress responses, providing additional biomarkers for therapeutic screening.
Overall, the findings establish hiPSC-RPE cells as a physiologically relevant and highly sensitive platform for studying oxidative stress, gene regulation, and disease pathways in the retina. The model offers significant opportunities for the development and testing of anti-VEGF therapies, gene-editing strategies, and other treatments targeting retinal diseases such as age-related macular degeneration (AMD).
Authors
Anni Kolehmainen, Robertas Čėsna, Olga Vergun, Dovilė Navickė, Giedrius Kalesnykas, Jenni J. Hakkarainen
