Fight Aging!

Regeneration from injury is an intricate dance of many different cell types: stem cells, somatic cells, cells that become senescent, and innate immune cells such as macrophages. This is true of every higher species, but what is the meaningful difference between species capable of regenerating entire limbs and internal organs, such as salamanders, and species that scar and exhibit only partial regeneration of lost tissue, such as near all mammals? In recent years, researchers have discovered that senescent cells and macrophages behave differently in injured tissues in species capable of proficient regeneration. Clearance of senescent cells is unusually efficient in salamanders, for example.

A characteristic of proficient tissue regeneration is a recapitulation of embryonic development, in which cells dedifferentiate to form a blastema in order to rebuild the structure of lost tissue. In today's open access paper, researchers find that salamander senescent cells produce signaling that encourages this dedifferentiation in muscle tissue during limb regeneration. Similar research in zebrafish, another highly regenerative species, has shown that senescent cells are necessary for regeneration of retinal tissues. While the senescence-associated secretory phenotype (SASP) produced by senescent cells is clearly different from species to species, identifying specific signal differences that may be involved in proficient regeneration, as here, is very much a work in progress.

Benefits of "Zombie" Cells: Senescent Cells Aid Regeneration in Salamanders

Senescent cells are cells that have permanently stopped dividing in response to cellular stress but have not died. As organisms age, the number of senescent cells in the body increases. This accumulation is currently considered one of the hallmarks of aging and has been linked to a variety of diseases, including cancer. A growing body of evidence suggests that senescent cells may also have beneficial effects, such as wound healing or preventing tissue scarring.

Salamanders have unique regeneration abilities and are able to re-grow many organs of their bodies, including lost limbs. To check if the presence of senescent cells influences the limb regeneration process, researchers found a way to modulate the number of senescent cells in the wound. The team observed that the presence of senescent cells enhanced the regeneration process. "When more senescent cells were present in the wound, the animals developed a larger regeneration bud, or - as we call it - blastema. This is a collection of cells that are going to form all the needed tissues in the new limb. The larger the blastema, the more cells are there to regrow the limb and the quicker the regeneration process. The presence of senescent cells seemed to 'fuel' the regeneration process."

"Our results show that senescent cells use cell-cell communication to influence the regeneration process. They secrete molecules that signal to mature muscle fibers to dedifferentiate into muscle progenitor cells. These cells can multiply themselves as well as differentiate into new muscle cells, thereby enhancing the regeneration process. This signaling appears to be an important part of promoting regeneration."

Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

Salamanders are able to regenerate their entire limbs throughout lifespan, through a process that involves significant modulation of cellular plasticity. Limb regeneration is accompanied by the endogenous induction of cellular senescence, a state of irreversible cell cycle arrest associated with profound non-cell-autonomous consequences. While traditionally associated with detrimental physiological effects, here, we show that senescent cells can enhance newt limb regeneration.

Through a lineage tracing approach, we demonstrate that exogenously derived senescent cells promote dedifferentiation of mature muscle tissue to generate regenerative progenitors. In a paradigm of newt myotube dedifferentiation, we uncover that senescent cells promote myotube cell cycle re-entry and reversal of muscle identity via secreted factors. Transcriptomic profiling and loss of function approaches identify the FGF-ERK signalling axis as a critical mediator of senescence-induced muscle dedifferentiation. While chronic senescence constrains muscle regeneration in physiological mammalian contexts, we thus highlight a beneficial role for cellular senescence as an important modulator of dedifferentiation, a key mechanism for regeneration of complex structures.