More Evidence for the Importance of Senescent Cell / Immune Cell Interactions in Proficient Regeneration

Studies of the biochemistry of wound healing in species capable of complete regeneration of limbs and organs, such as salamanders and zebrafish, has pointed to differences in the behavior of senescent cells and immune cells such as macrophages during the regenerative process. Senescent cells are created as a result of injury, and cleared soon afterward by immune cells. While they are present, they appear to assist in the processes of regrowth and repair. It is hoped that a sufficient understanding of the biochemistry of proficient regeneration in salamanders and zebrafish will lead to ways to recreate the ability of embryonic mammals to regenerate lost body parts. The capability is clearly there, but lost in adult life.

Zebrafish spontaneously regenerate their retinas in response to damage through the action of Müller glia (MG). Even though 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 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 Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging but are still metabolically active, releasing a variety of signaling molecules as part of the senescence-associated secretory phenotype.

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.