Reactive Oxygen Species Signaling Differentially Controls Wound Healing and Regeneration

Reactive oxygen species (ROS), such as hydrogen peroxide, are conserved and critical components of both wound healing and regeneration. Even though millions are affected each year by poor wound healing and an inability to restore functional tissue, how the same ROS-mediated signaling regulates these two different processes is not fully understood. Here, we investigate the role(s) of ROS during planarian wound healing and regeneration. We show ROS accumulate after injury and are required for wound closure (by promoting cytoskeletal movements) and regrowth (by promoting blastema formation). We found that different threshold levels of ROS regulate separate downstream targets to control wound healing ( jun-1 ) versus regeneration ( hsp70 ). By only manipulating ROS levels, we were able to control which injury-induced program was initiated: failure to close (chronic wound), healing only (no blastema), or full regeneration. Our results demonstrate that healing versus regenerative outcomes are based on differential ROS-mediated gene expression soon after injury. This study highlights ROS signaling as a potential therapeutic means to control wound repair mechanisms in multiple contexts. Therefore, investigating the mechanisms by which ROS control different tissue repair processes will be necessary not only for regenerative medicine but to improve clinical outcomes for chronic wounds and fibrosis.