In addition to attracting immune cells to the site of

In addition to attracting immune cells to the site of injury, ROS also participate in proliferative responses during compensatory proliferation and regeneration. In Xenopus tadpoles, tail amputation induces sustained production of ROS over the span of regeneration, and decreasing ROS levels, especially early on after amputation, resulting in impaired tail regeneration. Amputation-induced ROS are also produced via NADPH oxidases, and activate Wnt/β-catenin and FGF signaling, thus initiating regeneration (Fig. 4B) [67], [68]. The role of caspases in ROS production was not investigated in this model, however, caspase-3 activity was previously shown to be important for proliferation during the first 24h after amputation [14]. In adult zebrafish, caudal fin amputation causes sustained ROS production, unlike the transient ROS response observed after larval tail fin injury. ROS are immediately detected near the lesion after fin amputation, and are tightly regulated during the first 24h of regeneration, reaching a peak at 12 and 16h post amputation. This sustained ROS generation is specific for the regenerative response and is not observed during wound healing responses. In this regenerative response, ROS generated via enzymatic activity of NOX induce JNK activation and delayed apoptosis (Fig. 4B). Both of these parallel processes are important for blastema formation and compensatory proliferation of epithelial cells [69]. In addition to epithelial regeneration, ROS production induced by amputation of the caudal fin also induces neuro-regeneration. In larvae, increased H2O2 produced by DUOX1 at wound sites is important for peripheral sensory axon regeneration and re-innervation of the skin [70]. In adult zebrafish, sensory neurons, especially Schwann cells, induce H2O2 production via Hedgehog signaling post amputation, and this H2O2 stimulates the axonal growth and attracts peripheral GW311616 hydrochloride to the regenerating blastema [71]. In a genuine AiP model in Drosophila wing discs, ROS generation triggered in response to a transient pulse of apoptosis induced activation of JNK and p38 signaling in the surviving cells that resulted in expression of JAK/STAT pathway ligand Unpaired (Interleukin-6 (IL-6) homolog), leading to regeneration of lost tissue (Fig. 4B) [33]. Similarly, another study showed that following acute liver injury in mice, dying hepatocytes produced ROS that induced production of IL-11 (a member of IL-6 family of cytokines). IL-11 triggers activation of JAK/STAT signaling in healthy hepatocytes, which results in compensatory proliferation (Fig. 4B). However, it was not investigated whether involvement of caspases in hepatocytes was necessary for production of ROS or downstream expression of IL-11 in this model of liver injury [72]. In Hydra, ROS are produced immediately at the wound edges following bisection, and are important for injury-induced cell death and MAPK activation in the head regenerating tips [73]. In planaria, amputation of both the head and tail regions induces ROS production at the wound site, which is necessary for regeneration, patterning, polarization of proliferating cells, and early nervous system differentiation. This study provided the first evidence that ROS are involved in anterior body regeneration, and that production of ROS was independent of the orientation of the wound site [74]. In mice, partial hepatectomy induced ROS production is tightly regulated by modulating activities of NADPH oxidases and scavenging enzymes. During the regenerative phase, NOX4 is activated while PRxs and catalases are downregulated to facilitate increased H2O2 production. On the other hand, during the termination phase of regeneration, the level of NOX4 is reduced, and that of PRxs and catalases are induced to decrease H2O2 production. In this model, H2O2 triggers two distinct signaling events in a dose-dependent manner. Elevated H2O2 levels induced cell proliferation by activation of ERK signaling, and in contrast, low H2O2 concentrations promoted cell quiescence by activation of p38 signaling. Thus, activity of specific enzymes and dose-dependent signaling by H2O2 triggers the proliferation-quiescence switch to govern liver regeneration after hepatectomy [75].