Senescence induced cellular reprogramming drives cnidarian whole body regeneration in the absence of stem cells

Cell fate stability is essential for maintaining law and order in complex animals. However, high stability comes at the cost of reduced plasticity and, by extension, poor regenerative ability. This evolutionary trade off has resulted in modern animals being either simple, plastic, and regenerative, or complex, stable, and non regenerative. The mechanisms that mediate these traits remain unknown. We show that signaling from senescent cells can destabilize the differentiated state of neighboring somatic cells, reprogramming them back to stem cells that drive whole body regeneration in the cnidarian Hydractinia symbiolongicarpus. Pharmacological or genetic inhibition of senescence prevented reprogramming and regeneration. Induction of ectopic senescence resulted in supernumerary stem cells. Therefore, senescence signaling may be an ancient mechanism mediating cellular plasticity. Senescence-induced reprogramming has retained high efficiency in morphologically simple, yet highly regenerative, cnidarians but degenerated to a rudimentary state in many bilaterians. This loss may have rendered their cell fates more stable and thereby enabling the evolution of their complexity at the expense of regenerative powers. Understanding the senescence environment that promotes cellular reprogramming could provide a new avenue to enhance regeneration in mammals.