Early redox activities modulate Xenopus tail regeneration

Redox state sustained by reactive oxygen species (ROS) is crucial for regeneration; however, the interplay between oxygen (O-2), ROS and hypoxia-inducible factors (HIF) remains elusive. Here we observe, using an optic-based probe (optrode), an elevated and steady O-2 influx immediately upon amputation. The spatiotemporal O-2 influx profile correlates with the regeneration of Xenopus laevis tadpole tails. Inhibition of ROS production but not ROS scavenging decreases O-2 influx. Inhibition of HIF-1 alpha impairs regeneration and stabilization of HIF-1 alpha induces regeneration in the refractory period. In the regeneration bud, hypoxia correlates with O-2 influx, ROS production, and HIF-1 alpha stabilization that modulate regeneration. Further analyses reveal that heat shock protein 90 is a putative downstream target of HIF-1 alpha while electric current reversal is a de facto downstream target of HIF-1 alpha. Collectively, the results show a mechanism for regeneration via the orchestration of O-2 influx, ROS production, and HIF-1 alpha stabilization.