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Species such as salamanders and zebrafish are capable of regrowing lost limbs, fins, and organ tissue without scarring, leading to a fully functional replacement. Regeneration from injury is in general a complex dance of different cell types: immune cells, stem cells, somatic cells. Further, senescent cells play an important part in this process. In response to injury some cells enter a senescent state and their inflammatory secretions help to coordinate the process of regrowth. The senescent cells either self-destruct or are destroyed by the immune system shortly thereafter – though, of course, this process of clearance is not completely efficient, and that inefficiency has sizable consequences over the long term. That some senescent cells linger, and in increasing numbers as the immune system falters with age, is a contributing cause of degenerative aging.
Research into the details of proficient regeneration in a variety of species points to significant differences in the behavior of senescent cells and their interactions with other cell types. Salamanders, for example, exhibit highly efficient clearance of senescent cells by immune cells following regeneration. A prehaps similar situation is present in African spiny mice, which are capable of more extensive regeneration than is the case for most mammals. In today’s open access research, the focus is on zebrafish, and the authors show that removal of a sizable fraction of senescent cells via senolytic treatment impairs regrowth but doesn’t prevent it. It would be interesting to see the outcome of complete clearance of senescent cells.
Cellular senescence is a terminal cell response consisting on the implementation of a permanent cell cycle arrest and the acquisition of a secretory phenotype with cell-to-cell communication properties. Exhaustion of the proliferative capacity of the cell leads to senescence, and the accumulation of these damaged cells in tissues from old individuals is considered a key element in the process of aging. Despite this detrimental effect, the senescence response has a beneficial side protecting damaged cells from proliferating. This is considered the basis of its tumor-suppressive function. The recent identification of developmentally programmed cell senescence during embryogenesis expanded our view of the positive activities of this response. Senescence during development promotes cell turnover, tissue remodeling, and, paradoxically, growth. A similar positive pro-morphogenetic activity for cell senescence has been suggested to operate during skin wound healing in mice and during limb regeneration in salamanders. Senescent cells seem to appear at wound sites after injury to help promote optimal wound healing.
Here, we decided to evaluate the senescence response in the context of tissue injury using an animal model of complex tissue regeneration, the zebrafish. To study senescence after tissue damage, we amputated the pectoral fin of adult fish (around 1 year old) at approximately 50% of its length and followed regeneration with time. We stained fins for senescence-associated beta-galactosidase (SAbetaGal), the most widely used marker of senescence, after 8, 16, or 30 days postamputation (dpa), a time point in which fins were completely regenerated. Fins at 8 dpa showed intense blue staining compared with light blue at 16 dpa and completely absent staining at 30 dpa. We observed that 8 dpa was the time point that produced a stronger SAbetaGal reaction and this activity was restricted to the distal part of the fin, the area where regeneration takes place. These results support the notion of a transient induction of cell senescence during fin regeneration.
To directly assess the role of senescence induction during fin amputation, we decided to induce the removal of these senescent cells from amputated fins. For this, we treated fish for 48 or 72 hr with ABT-263 (Navitoclax), a senolytic compound that by inhibiting the Bcl-2 antiapoptotic family of proteins triggers specifically the death of the senescent cell. ABT-263 treatment caused a reduction in SAbetaGal staining and a concomitant induction of apoptosis in the regenerating area. We determined the regenerative capacity by measuring the length of regenerate at 8 dpa in fish treated with ABT-263. This analysis revealed that the removal of senescent cells by ABT-263 treatment clearly impaired regeneration, with amputated fins in fish treated with ABT-263 showing a clear reduction in the length of regenerate compared with the one reached in control animals.
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