Bystander effects elicited by single-cell photo-oxidative blue-light stimulation in retinal pigment epithelium cell networks

‘Bystander effect’ refers to the induction of biological effects in cells not directly targeted. The retinal pigment epithelium consists of hexagonal cells, forming a monolayer interconnected by gap junctions (GJs). Oxidative stress initiated in an individual cell by photostimulation (488 nm) triggered changes in reactive oxygen species (ROS), Ca(2+) and mitochondrial membrane potential (ψ(m)). The Ca(2+) signal was transmitted to neighboring cells slowly and non-uniformly; the ROS signal spread fast and radially. Increased Ca(2+) levels were associated with a loss in ψ(m). GJ blockers prevented the spreading of the Ca(2+), but not the ROS-related signal. The GJ-mediated Ca(2+) wave was associated with cell death by 24 h, requiring endoplasmic reticulum–mitochondria Ca(2+) transfer. Ensuing cell death was correlated with baseline Ca(2+) levels, and baseline Ca(2+) levels were correlated with pigmentation. Hence, local oxidative stress in a donor cell can trigger changes in certain connected recipient cells, a signal that required GJ communication and an ROS-Ca(2+) dual-hit. Finally, damage apparently occurred in susceptible cells, which correlated with baseline Ca(2+) levels.