Systemic Cell Cycle Re-entry Following Amputation in Axolotl: Consequence and Mechanism.

Axolotl salamanders fully regenerate limbs following amputation throughout life. These limbs are anatomically similar to human limbs. Thus, understanding the molecular and cellular biology of axolotl limb regeneration will provide a road map for how tetrapod limbs naturally regenerate, with the hope of spurring future therapeutic approaches in human. Most research has focused on cellular events at the site of amputation since the progenitor cells that are used as building blocks reside nearby. However, we recently discovered a body-wide cell proliferation, "systemic activation," response to amputation in axolotl, which is separable from successful regeneration. We will present new experiments demonstrating that amputation primes other limbs for faster future regeneration, representing a possible selective advantage for this process. We will present work implicating the peripheral nervous system, as well as adrenergic and insulin signaling, in transmitting amputation-injury information to distant tissues. We also show that mTOR signaling is essential for systemic activation in response to amputation in axolotl. We will discuss these findings with respect to known regenerative responses, and more limited injury responses without full appendage regeneration, in other species. Overall, our research supports a two-step model whereby putative progenitor cells are broadly activated following amputation, but only some highly-regenerative species go on to refine this response to the local site of injury to enable regeneration of a lost body part.