Understanding the molecular mechanisms that promote successful tissue regeneration is critical for continued advancements in regenerative medicine. Vertebrate amphibian tadpoles of the species Xenopus laevis and Xenopus tropicalis have remarkable abilities to regenerate their tails following amputation1,2, through the coordinated activity of numerous growth factor signalling pathways, including the Wnt, Fgf, Bmp, Notch and TGF-β pathways3,4,5,6. Little is known, however, about the events that act upstream of these signalling pathways following injury. Here, we show that Xenopus tadpole tail amputation induces a sustained production of reactive oxygen species (ROS) during tail regeneration. Lowering ROS levels, using pharmacological or genetic approaches, reduces the level of cell proliferation and impairs tail regeneration. Genetic rescue experiments restored both ROS production and the initiation of the regenerative response. Sustained increased ROS levels are required for Wnt/β-catenin signalling and the activation of one of its main downstream targets, fgf20 (ref. 7), which, in turn, is essential for proper tail regeneration. These findings demonstrate that injury-induced ROS production is an important regulator of tissue regeneration.
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We thank P. Niethammer (Sloan-Kettering Institute, USA) for the pCS2+ HyperYFP construct, the University of Manchester Bioimaging Facility for guidance with imaging, and R. Paredes and Y. Matsubayashi for advice on statistical analyses. We also thank N. Papalopulu and C. Thompson for comments on the manuscript. This work was supported by a Wellcome Trust Program Grant (E.A.), a Wellcome Trust Career Development Fellowship (J.L.G.), a Wellcome Trust PhD Studentship (P.K.), and grants from the BBSRC (K.D.), The Healing Foundation (N.R.L., Y.C., E.A.) and The National Science Foundation (N.R.L.).
The authors declare no competing financial interests.
Supplementary Information (PDF 1198 kb)
Simultaneous imaging of HyPerYFP and RFP labeled inflammatory cells for the first 6 h following tail amputation.
Upper left panel shows transillumination, lower left panel shows HyPerYFP ratio, upper right panel shows RFP labelled inflammatory cells, lower right panel shows RFP labelled inflammatory cells and their tracked migratory behaviour. Images were captured at one-minute intervals. (MOV 33848 kb)
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Love, N., Chen, Y., Ishibashi, S. et al. Amputation-induced reactive oxygen species are required for successful Xenopus tadpole tail regeneration. Nat Cell Biol 15, 222–228 (2013). https://doi.org/10.1038/ncb2659
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