Adrenergic signaling stimulates body-wide stem cell activation for limb regeneration

Many species throughout the animal kingdom naturally regenerate complex body parts following amputation. Most research in appendage regeneration has focused on identifying mechanisms that influence cell behaviors in the remaining stump tissue, immediately adjacent to the injury site. Roles for activation steps that occur outside of the injury site remain largely unexplored, yet they may be critical for successful regeneration. Here, we discovered a role for adrenaline in stimulating a body-wide stem cell activation response to amputation that drives limb regeneration. Notably, this systemic response is mediated by engagement of the peripheral nervous system (PNS) and adrenergic signaling at both the injury site and in distant, uninjured tissues. This work challenges the predominant conceptual framework considering the injury site alone in the regenerative response, arguing instead for body-wide stem cell activation as a priming step upon which molecular cues at the injury site then build tissue. ### Competing Interest Statement J. Whited is a co-founder of Matice Biosciences.