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Many species regenerate lost body parts following amputation. Most limb regeneration research has focused on the immediate injury site. Meanwhile, body-wide injury responses remain largely unexplored but may be critical for regeneration. Here, we discovered a role for the sympathetic nervous system in stimulating a body-wide stem cell activation response to amputation that drives enhanced limb regeneration in axolotls. This response is mediated by adrenergic signaling, which coordinates distant cellular activation responses via the α -adrenergic receptor, and local regeneration responses via β-adrenergic receptors. Both α - and β-adrenergic signaling act upstream of mTOR signaling. Notably, systemically-activated axolotls regenerate limbs faster than naïve animals, suggesting a potential selective advantage in environments where injury from cannibalism or predation is common. This work challenges the predominant view that cellular responses underlying regeneration are confined to the injury site and argues instead for body-wide cellular priming as a foundational step that enables localized tissue regrowth.

Animals exhibit extreme diversity in regenerative ability. This likely reflects different, lineage-specific selective pressures in their evolutionary histories, but how specific molecular features of regenerative programs help solve species-specific challenges has not been examined in detail. Here we discover that, in the highly-regenerative axolotl salamander, a conserved, body-wide stem cell activation response triggered in response to limb removal primes undisturbed limbs for regeneration upon subsequent amputation. This response should be particularly useful to salamanders, which frequently lose limbs in response to cannibalism. We further demonstrate the body-wide response requires both peripheral nervous system input at these distant sites and mTOR signaling. We defined gene expression changes within the nerves and nearby tissues, harboring responsive stem cells, leading to identification of candidate genetic pathways influencing distant stem cell activation following amputation. Functional experimentation confirmed a requirement for adrenergic signaling in amputation-induced activation of distant stem cells. These findings reveal a direct link between systemic cellular activation responses to local tissue damage and overall regenerative ability. Similar systemic activation responses to tissue removal have been observed in animals with widely differing regenerative abilities (e.g., planaria to mice), suggesting that it is the responses downstream of these signals, likely sculpted by differing evolutionary pressures, that ultimately distinguish regenerators from non-regenerators. Competing Interest Statement J. Whited is a co-founder of Matice Biosciences.

Pure and different percentages (0.25, 0.5, 1.0, and 2.5%) of silver (Ag) doped hydroxyapatites (Hap) were synthesized employing the wet chemical precipitation method. The samples were characterized with the aid of X‐ray diffraction (phase analysis, crystallographic characterization, and crystal size calculation using Scherrer equation and different models), scanning electron microscopy, and optical bandgap energy. The Hap containing 0.25% Ag showed better photocatalytic activity in various dye concentrations, catalyst doses, and pH. At a very low catalyst dose (0.375 g/L) and 20 ppm pollutant concentration, reaction rate, and rate constant were evaluated for the Congo Red dye, ciprofloxacin, amoxicillin, and levofloxacin. The maximum rate constant (0.0028 min−1) and reaction rate (9.657 × 10−8 mole L−1·min−1) were found for Congo Red dye and ciprofloxacin, respectively, using 0.25_Ag‐Hap (0.25% Ag‐doped Hap). The energies of the valance band (3.14 eV) and conduction band (−0.36 eV) were lower in the case of 0.25_Ag‐Hap than the other samples. Simplified reaction mechanisms were proposed for the photocatalytic degradation of Congo Red dye, ciprofloxacin, amoxicillin, and levofloxacin. Silver doping enhances the photocatalytic activity of nanocrystalline hydroxyapatite.