Connective tissue fibroblasts from highly regenerative mammals are refractory to ROS-induced cellular senescence

Sandeep Saxena; Hemendra Vekaria; Patrick G. Sullivan; Ashley W. Seifert

doi:10.1038/s41467-019-12398-w

Connective tissue fibroblasts from highly regenerative mammals are refractory to ROS-induced cellular senescence

Sandeep Saxena, Hemendra Vekaria, Patrick G. Sullivan, Ashley W. Seifert

Research output: Contribution to journal › Article › peer-review

73 Scopus citations

Abstract

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.

Original language	English
Article number	4400
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12398-w
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

We thank all members of the Seifert lab for insightful discussions, Thomas Gawriluk and Shishir Biswas for help with comparative genomics, Fatemah Safaee for help with routine cell culture, Adam Cook for animal husbandry, Xiang Liang for help with irradiation experiments, Katherine Thompson, Arnold Stromberg, and Aviv Brockman for consultation on statistical analysis. 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.

Funders	Funder number
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Science Foundation Arctic Social Science Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01AR070313
Office of International Science and Engineering	IOS-1353713

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-019-12398-w

Cite this

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abstract = "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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AU - Vekaria, Hemendra

AU - Sullivan, Patrick G.

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Connective tissue fibroblasts from highly regenerative mammals are refractory to ROS-induced cellular senescence

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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