Zombie upside – senescent cells aid regeneration in salamanders

Scientists show that senescent cells boost production of new muscle cells to enhance regeneration of lost limbs in salamanders.

Senescence, the permanent cessation of cell division in response to cellular stress, has long been associated with aging and various diseases, including cancer. However, recent research at the Technische Universität Dresden has shed light on the complex and context-dependent nature of senescent cells – often nicknamed zombie cells since they don’t die and induce others to enter the same state.

Longevity.Technology: As we age, the number of senescent cells in the body increases, an accumulation that is considered to be one of the hallmarks of aging. This accumulation of senescent cells can affect a person’s ability to withstand stress or illness, repair injuries and wear and tear, and it can also cause degradation of cognitive functions. Cellular senescence has been implicated to myriad age-related conditions, including Alzheimer’s, diabetes, osteoporosis, cardiovascular disease, stroke, osteoarthritis and cancer.

However, senescence is not all bad. The senescent secretome – the molecules and compounds expressed by senescent cells – have been shown to play various significant roles throughout our lives, including in embryonic development, and contrary to the traditional view of senescence as solely detrimental, evidence suggests that these cells may also play beneficial roles in processes such as wound healing and tissue regeneration.

One area of study that has yielded intriguing findings is the investigation of senescent cells in the context of limb regeneration in salamanders. Dr Maximina Yun, research group leader at the Center for Regenerative Therapies Dresden (CRTD) and the Cluster of Excellence Physics of Life (PoL) at TU Dresden and the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), explains: “A few years ago, our group found that senescent cells were present at key stages of salamander limb regeneration. Interestingly, other groups subsequently found these cells in other regeneration contexts, including in mammals. We therefore wanted to find out whether these cells contribute in any way to regeneration itself [1].”

To investigate the influence of senescent cells on limb regeneration, the researchers in Dr Yun’s group manipulated the number of senescent cells present in the wound, discovering that an increased presence of senescent cells led to the development of a larger regeneration bud, or blastema, which consists of cells that give rise to the new tissues in the regenerated limb. This observation, says Dr Yun, suggests that senescent cells ‘fuel’ the regeneration process.

Looking more closely at the blastema, both with and without the influence of the senescent cells, the Yun team uncovered a new mechanism by which senescent cells enhance regeneration. Their findings revealed that senescent cells secrete factors that stimulate nearby muscle tissue to revert to an earlier developmental stage and produce new muscle cells [2].

Zombie upside – senescent cells aid regeneration in salamanders
Photograph: Maximina Yun

Dr Yun notes: “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 [1].”

While the focus of this study was on muscle regeneration, the researchers are also exploring whether senescent cell signaling contributes to the regeneration of other tissues. By gaining insights from salamander regeneration abilities, scientists hope to uncover principles that can be applied to improve human regenerative potential.

The study of senescence and its impact on regeneration and aging processes offers valuable lessons. Salamanders, known for their extraordinary healing abilities and lack of typical signs of aging and age-related diseases, present an intriguing model for understanding the mechanisms behind regeneration.

Dr Yun explains: “Salamanders are one of the few animal species that seem to defy the natural aging process. They do not develop typical signs of aging and do not accumulate age-related diseases such as cancer. They also have extraordinary healing abilities [1].”

Extraordinary is the right word – salamanders can regenerate almost any organ in their body.

Research into senescence continues to uncover its intricacies; it holds promise for the development of potential therapeutics that could enhance regeneration and improve healthspan, and by deciphering the signaling mechanisms and factors involved in senescent cell-induced regeneration, scientists may unlock strategies to promote tissue repair and regeneration in humans, thus counteracting counteract the effects of aging-related diseases.

[1] https://bit.ly/3JrLE8c
[2] https://onlinelibrary.wiley.com/doi/10.1111/acel.13826

Photograph: brgfx/Envato