iPSC-derived RPE cells from donors were used to study the combined effects of genetic and environmental AMD risks.

The CFH Y402H high genetic risk for AMD renders RPE cells more vulnerable to oxidative stress from the cigarette smoke component Hydroquinone.

Age-related macular degeneration (AMD) is one of the main causes of blindness in the elderly population and is caused by a combination of risk factors: genetic predisposition, aging and lifestyle factors, such as smoking. One of the main genetic risks includes the Y402H polymorphism in complement Factor H (FH), an inhibitor of complement system activation. Retinal pigment epithelium (RPE) cells play a central role in the development of AMD. 

In this study, researchers at the IOR Tübingen employed RPE cells derived from induced pluripotent stem cells (iPSC) generated from donors, carrying either homozygous 402Y (low risk) or 402H (high risk) variants of the CFH gene. iPSC were provided by collaborating scientists at CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa, Sevilla, Spain) and NEI (National Eye Institute, Bethesda, USA), and iPSC-derived RPE (iPSC-RPE) generated at the IOR in Tübingen. The mature iPSC-RPE cells retain characteristics of RPE cells of the human eye and are a valuable model to study disease pathology.

To better mimic the life-style risk component of AMD, RPE cells were treated with Hydroquinone (HQ), a component of cigarette smoke, inducing oxidative stress. Results proved that high risk (HR) RPE cells are more vulnerable to HQ-mediated stress. Importantly, HQ-mediated damage in HR-RPE cells is most likely conferred by intracellular FH, a novel aspect of complement system biology, relevant for future therapeutic interventions.

The data suggest that the ability of FH to protect RPE cells from oxidative stress is impaired by the AMD high risk 402H variant. This completely novel function of FH is relevant for the design of new therapeutic avenues for AMD, especially with regard to future personalized medicine approaches targeting patients with a specific genotype. 

Here is the link to the original publication: “The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells” 
by Angela Armento, Inga Sonntag, Ana-Cristina Almansa-Garcia, Merve Sen, Sylvia Bolz, Blanca Arango-Gonzalez, Ellen Kilger, Ruchi Sharma, Kapil Bharti, Rosario Fernandez-Godino, Berta de la Cerda, Simon J. Clark, Marius Ueffing