GSE192477
Systemic stem cell activation following amputation primes distant appendages for future regeneration events in axolotl
A remarkable diversity in regenerative competency of extant species suggests an evolutionary influence, but few studies have identified potential selective pressures shaping this variation. Uncovering these selective pressures is critical to understanding the key molecular similarities, and differences, between regeneratorsand non-regenerators. Here we report that, in the highly-regenerative axolotl, an evolutionarily conserved body-wide stem cell activation response primes other limbs for faster regeneration, offering a selective advantage for this phenomenon. We further demonstrate the body-wide response requires peripheral nervous system input at these distant sites and is predicated on mTOR signaling. We definedgene expression changes within the signaling neural processes and nearby tissues, harboring responsive stem cells, leading to candidate genetic pathways central to this process. Functional experimentation confirmed a requirement for adrenergic signaling in amputation-induced activation of distant stem cells. Our study provides a direct link between body-wide cellular activation responses and regeneration, unifying previous reports from distant species of various natural regenerative abilities, such as planarians and mice, in a conceptual framework that centers the ability to convert the body-wide response to local tissue outgrowth as the key difference between regenerators and non-regenerators. Overall design: 18 forelimb samples in total split into 2 cases: 4 denervated nerve vs 3 sham nerve, then 7 denervated surrounding tissue vs 4 sham surrounding tissue.  In all cases the denervated samples were compared to sham as a baseline.  The samples were aligned to an index of a Transcriptome (Bryant et al., Cell Reports, 2017.)