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Systemic stem cell activation following amputation primes distant appendages for future regeneration events in axolotl

ABSTRACT: 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.

ORGANISM(S): Ambystoma mexicanum

PROVIDER: GSE192477 | GEO | 2022/01/01

REPOSITORIES: GEO

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Project description:Variability of regenerative potential among animals has long perplexed biologists. Based on their amazing regenerative abilities, planarians have become important models for understanding the molecular basis of regeneration; however, planarian species with limited regenerative abilities are also found. Despite the importance of understanding the differences between closely related, regenerating and non-regenerating organisms, few studies have focused on the evolutionary loss of regeneration, and the molecular mechanisms leading to such regenerative loss remain obscure. Here we examine Procotyla fluviatilis, a planarian with restricted ability to replace missing tissues, utilizing next-generation sequencing to define the gene expression programs active in regeneration-permissive and regeneration-deficient tissues. We found that Wnt signaling is aberrantly activated in regeneration-deficient tissues. Remarkably, down-regulation of canonical Wnt signaling in regeneration-deficient regions restores regenerative abilities: blastemas form and new heads regenerate in tissues that normally never regenerate. This work reveals that manipulating a single signaling pathway can reverse the evolutionary loss of regenerative potential. RNA-seq experiments to identify gene expression changes following amputation in body regions with variable regenerative potential. Adult Procotyla fluviatilis were amputated at sites either anterior or posterior to the pharynx. After 24 hours post-amputation, tissues near the amputation site were excised and RNA was extracted. Similar tissues were excised from uncut control animals. Samples were processed for RNA-seq using Illumina procedures. We generated a de novo P. fluviatilis transcriptome and used RNA sequencing (RNA-seq) to characterize transcripts from excised tissue fragments in Reg+ and Reg- body regions 24 hours post-amputation. We performed parallel analyses on tissues excised from intact animals at identical body regions to account for regional differences in transcripts, thereby identifying changes resulting from amputation. Samples A1-A3 = Regeneration-proficient (Reg+) tissue excision 24 hours after amputation. Samples B1-B3 = Tissue excision from regeneration-proficient (Reg+) region but not amputated. Samples C1-C3 = Tissue excision from regeneration-deficient (Reg-) tissues 24 hours after amputation. Samples D1, D3-D4 = Tissue excision from regeneration-deficient (Reg-) region that was not amputated.

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Systemic stem cell activation following amputation primes distant appendages for future regeneration events in axolotl

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