Senescent Cells in Proficient Regeneration of Organs
Some higher species, such as salamanders and zebrafish, are capable of complete regeneration of damage to organs as adults, including central nervous system tissue such as the retina. In mammals, with a very few limited exceptions, this type of regeneration is only possible during embryonic development. Is it possible to enable adult mammals to regenerate like zebrafish through some adjustment to the regulation of genes? That is the reason why researchers are attempting to understand the cellular differences that enable proficient regeneration. In recent years, attention has focused on the interaction of macrophages and senescent cells during wound healing, suggesting that something in their behavior is important for regeneration.
Zebrafish spontaneously regenerate their retina in response to damage through the action of Müller glia. Even though Müller glia (MG) are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration with precise temporal roles for macrophages and microglia.
Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging, but are still metabolically active, releasing pro-inflammatory signaling molecules as part of the Senescence Associated Secretory Phenotype (SASP). Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia/macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after damage.
Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.