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.

DNA repair during regeneration in Ambystoma mexicanum

“…65 Nevertheless, it is well known that ROS are able to induce a plethora of insults inside the cell, in specific they are capable to affect the DNA molecule and activate the DDR resulting in stress-induced senescence. Interestingly, Saxena et al 66 determined that fibroblasts from mammalian species (Acomys cahirinus and Oryctolagus cuniculus) with remarkable regeneration capabilities can resist H 2 O 2 treatments preventing senescence and the associated DNA damage, as well as avoiding oxidative stress induced-mitochondrial dysfunction, this oxidative F I G U R E 2 Possible outcomes for progenitor and stem cells with damaged DNA. A healthy stem cell can be affected in their DNA integrity due to external and internal sources, once this cell has accumulated an irreparable or unbearable DNA damage it could follow different pathways to deal with it such as, turn it-self into a senescent cell, undergo apoptosis, differentiates or develop a tumorigenesis process, all of them with the potential of exhausting the cells pool and therefore affect the regeneration resilience is accomplished through the implementation of enhanced detoxification methods.…”

Mitochondria exert age-divergent effects on recovery from spinal cord injury

“…Specifically, a biproduct of mitochondrial respiration is the generation of reactive oxygen species (ROS), which under normal physiological conditions function in vital cell signaling. In excess however, increases in ROS drive pathophysiological processes such as protein and lipid oxidation that can induce senescence and accelerate disease pathology ( Birla et al, 2020 ; Cherubini et al, 2020 ; Hall et al, 2015 ; Ricke et al, 2020 ; Saxena et al, 2019 ; Zhang et al, 2019 ).…”

Biodegradable hollow mesoporous organosilica nanotheranostics (HMON) for multi-mode imaging and mild photo-therapeutic-induced mitochondrial damage on gastric cancer

“…In order to further confirm whether the mitochondrial-damage-dependent apoptosis pathway contributed by HMON@CuS/Gd induced PDT effect, N -Acetyl- l -cysteine (NAC, an anti-oxidant containing sulfhydryl group) was applied for the rescue experiments [ 49 ]. With the addition of NAC, intracellular ROS level in HMON@CuS/Gd plus NIR treated HGC-27 cells was dramatically decreased (Fig.…”