Emergence of large-scale cell death through ferroptotic trigger waves

Area of Science:

• Cell Biology
• Developmental Biology
• Pathology

Background:

• Large-scale cell death is crucial in development and disease.
• Coordinating widespread cell death spatially and temporally is a key question.
• Trigger waves are known for long-range signaling but their role in cell death was unclear.

Purpose of the Study:

• To investigate if ferroptosis can propagate via trigger waves.
• To elucidate the mechanisms controlling ferroptosis wave propagation.
• To explore the role of ferroptosis in embryonic development.

Main Methods:

• Utilized human cell cultures and chemical/genetic perturbations.
• Measured ferroptosis propagation distances and speeds.
• Analyzed reactive oxygen species (ROS) feedback loops and cellular redox states.
• Observed ferroptosis during embryonic avian limb development.

Main Results:

• Ferroptosis propagated over long distances (≥5 mm) at constant speeds (~5.5 μm/min) via ROS trigger waves.
• ROS feedback loops (Fenton reaction, NADPH oxidase, glutathione synthesis) are critical for wave progression.
• Suppression of cystine uptake induced bistability in cellular redox systems, enabling ROS propagation.
• Ferroptosis propagation was observed during embryonic avian limb muscle remodeling.

Conclusions:

• Ferroptosis can be coordinated over large cell populations through ROS trigger waves.
• ROS feedback loops and redox bistability are key regulators of ferroptosis wave propagation.
• Ferroptosis acts as a tissue-sculpting mechanism during embryogenesis.
• This provides a framework for studying large-scale cell death in development and pathology.