A surveillance system in mammals constantly monitors cell activity to protect against aberrant proliferation in response to damage, injury and oncogenic stress. Here we isolate and culture connective tissue fibroblasts from highly regenerative mammals (Acomys and Oryctolagus) to determine how these cells interpret signals that normally induce cellular senescence in non-regenerating mammals (Mus and Rattus). While H2O2 exposure substantially decreases cell proliferation and increases p53, p21, p16, and p19 in cells from mice and rats, cells from spiny mice and rabbits are highly resistant to H2O2. Quantifying oxygen consumption and mitochondrial stability, we demonstrate that increased intracellular H2O2 is rapidly detoxified in regenerating species, but overwhelms antioxidant scavenging in cells from non-regenerative mammals. However, pretreatment with N-acetylcysteine (NAC) protects mouse and rat cells from ROS-induced cellular senescence. Collectively, our results show that intrinsic cellular differences in stress-sensing mechanisms partially explain interspecific variation in regenerative ability.

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Published in Nature Communications, v. 10, article no. 4400.

© The Author(s) 2019

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This work was supported by grants from the National Science Foundation (NSF) and the Office for International Science and Engineering (OISE) (IOS-1353713) and from the National Institute of Musculoskeletal, Arthritis, and Skin Diseases (NIAMS) (R01AR070313) to A.W.S. The content in this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or National Science Foundation.

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