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

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.

SUBMITTER: Saxena S

PROVIDER: S-EPMC6764955 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Saxena Sandeep S Vekaria Hemendra H Sullivan Patrick G PG Seifert Ashley W AW

Nature communications 20190927 1

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 H<sub>2</sub>O<sub>2</sub> exposure substantially decreases cell proliferation and ...[more]

PMID: 31562333

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Project description:ObjectiveConnective tissue growth factor (CTGF) is a cysteine-rich secreted matricellular protein involved in wound healing and tissue repair. Enhanced and prolonged expression of CTGF has been associated with tissue fibrosis in humans. However, questions remain as to whether CTGF expression alone is sufficient to drive fibrosis. This study was undertaken to investigate whether CTGF alone is sufficient to cause fibrosis in intact animals and whether its effects are mediated through activation of transforming growth factor beta (TGFbeta) signaling or through distinct signal transduction pathways.MethodsWe generated mice overexpressing CTGF in fibroblasts under the control of the fibroblast-specific collagen alpha2(I) promoter enhancer. Tissues such as skin, lung, and kidney were harvested for histologic analysis. Mouse embryonic fibroblasts were prepared from embryos (14.5 days postcoitum) for biochemical analysis.ResultsMice overexpressing CTGF in fibroblasts were susceptible to accelerated tissue fibrosis affecting the skin, lung, kidney, and vasculature, most notably the small arteries. We identified a marked expansion of the myofibroblast cell population in the dermis. RNA analysis of transgenic dermal fibroblasts revealed elevated expression of key matrix genes, consistent with a fibrogenic response. CTGF induced phosphorylation of p38, ERK-1/2, JNK, and Akt, but not Smad3, in transgenic mouse fibroblasts compared with wild-type mouse fibroblasts. Transfection experiments showed significantly increased basal activity of the CTGF and serum response element promoters, and enhanced induction of the CTGF promoter in the presence of TGFbeta.ConclusionThese results demonstrate that selective expression of CTGF in fibroblasts alone causes tissue fibrosis in vivo through specific signaling pathways, integrating cues from the extracellular matrix into signal transduction pathways to orchestrate pivotal biologic responses relevant to tissue repair and fibrosis.

Dataset Information

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

Publications

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

Similar Datasets

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