Description
Large-scale cell death is commonly observed during organismal development and human pathologies. These cell death events extend over great distances to eliminate large populations of cells, raising the question of how cell death can be coordinated in space and time. One mechanism that enables long-range signal transmission is trigger waves, but how it might be utilized for death events in cell populations remains elusive. Here, we demonstrate that ferroptosis, an iron and lipid peroxidation-dependent form of cell death, can propagate across human cells over long distances (≥ 5 mm) at constant speeds (~ 5.5 μm/min) via trigger waves of reactive oxygen species (ROS). Chemical and genetic perturbations indicate a primary role of ROS feedback loops (Fenton reaction, NADPH oxidase signaling, and glutathione synthesis) in controlling the progression of ferroptotic trigger waves. We show that introducing ferroptotic stress via suppression of cystine uptake activates these ROS feedback loops, converting cellular redox systems from being monostable to bistable, thereby priming cell populations to become bistable media over which ROS propagate. Furthermore, we demonstrate that ferroptosis and its propagation accompanies the massive, yet spatially-restricted, cell death events during muscle remodeling of the embryonic avian limb, substantiating its utility as a tissue-sculpting strategy during embryogenesis. Our findings highlight the role of ferroptosis in coordinating global cell death events, providing a paradigm for investigating large-scale cell death in embryonic development and human pathologies.
