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PreprintCC BY-NDbioRxiv

Limb-localized induction of regeneration reshapes brain and amputation-site transcriptional states in adult Xenopus laevis

  • Stewart J. Russell1
  • Kelsie A. Miller2
  • David L. Kaplan3,4
  • Michael Levin2,4
  • Nirosha J. Murugan1,4
4 affiliations
  1. 1Department of Health Sciences, Wilfrid Laurier University, Waterloo ON, Canada
  2. 2Department of Biology, Tufts University, Medford, MA, USA
  3. 3Department of Biomedical Engineering, Tufts University, Medford, MA, USA
  4. 4Allen Discovery Center at Tufts University, Medford, MA, USA
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Abstract

Limb regeneration requires coordinated tissue reconstruction and nervous system reintegration, yet whether regenerative induction alters brain responses to limb loss remains unclear. We analyzed transcriptomics from the paired brains and amputation sites of adult Xenopus laevis after hindlimb amputation with or without a 24 hour exposure to localized, pro-regenerative multi-drug treatment (MDT) delivered through a wearable bioreactor device. At 24 hours post treatment (24 HPT), MDT brains showed increased vascular and basement membrane transcripts and enrichment of oxidative phosphorylation and mTORC1 programs. In the limb, an exploratory integrated stress response (ISR) score increased at 11 and 24 HPT and returned to control levels by 7 days post-treatment (7 DPT), coinciding with induction of growth differentiation factor 15 (GDF15), a cytokine responsive to mitochondrial stress. We detected no corresponding increase in brain ISR score. At 7 DPT, MDT brains showed enrichment of immune, heme metabolism and biosynthetic programs, reduced synaptic transmission gene expression, and increased gdf15.L. Relative to an external uninjured reference, MDT and amputation only brains showed concordant changes, with treatment modifying selected programs. Cross-species comparative analyses identified partial overlap with an axolotl regenerative glutamatergic signature and separation from selected mammalian injury profiles. These findings reveal cross-tissue responses to regenerative induction and identify candidate mechanisms of brain body communication in biomedically engineered vertebrate limb regeneration.

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Cite

BibTeXRIS
BibTeX
@misc{russell2026limblocalized,
  title = {{Limb-localized induction of regeneration reshapes brain and amputation-site transcriptional states in adult Xenopus laevis}},
  author = {Stewart J. Russell and Kelsie A. Miller and David L. Kaplan and Michael Levin and Nirosha J. Murugan},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.23.761414},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.23.761414v1},
  note = {CC BY-ND},
}
RIS
TY  - UNPB
TI  - Limb-localized induction of regeneration reshapes brain and amputation-site transcriptional states in adult Xenopus laevis
AU  - Stewart J. Russell
AU  - Kelsie A. Miller
AU  - David L. Kaplan
AU  - Michael Levin
AU  - Nirosha J. Murugan
PY  - 2026
DA  - 2026/10/23
PB  - bioRxiv
DO  - 10.64898/2026.10.23.761414
UR  - https://www.biorxiv.org/content/10.64898/2026.10.23.761414v1
AB  - Limb regeneration requires coordinated tissue reconstruction and nervous system reintegration, yet whether regenerative induction alters brain responses to limb loss remains unclear. We analyzed transcriptomics from the paired brains and amputation sites of adult Xenopus laevis after hindlimb amputation with or without a 24 hour exposure to localized, pro-regenerative multi-drug treatment (MDT) delivered through a wearable bioreactor device. At 24 hours post treatment (24 HPT), MDT brains showed increased vascular and basement membrane transcripts and enrichment of oxidative phosphorylation and mTORC1 programs. In the limb, an exploratory integrated stress response (ISR) score increased at 11 and 24 HPT and returned to control levels by 7 days post-treatment (7 DPT), coinciding with induction of growth differentiation factor 15 (GDF15), a cytokine responsive to mitochondrial stress. We detected no corresponding increase in brain ISR score. At 7 DPT, MDT brains showed enrichment of immune, heme metabolism and biosynthetic programs, reduced synaptic transmission gene expression, and increased gdf15.L. Relative to an external uninjured reference, MDT and amputation only brains showed concordant changes, with treatment modifying selected programs. Cross-species comparative analyses identified partial overlap with an axolotl regenerative glutamatergic signature and separation from selected mammalian injury profiles. These findings reveal cross-tissue responses to regenerative induction and identify candidate mechanisms of brain body communication in biomedically engineered vertebrate limb regeneration.
SN  - 2692-8205
ER  -