Adrenergic signaling coordinates distant and local responses to amputation in axolotl

Duygu Payzin-Dogru¹, Tim Froitzheim¹, Steven J Blair¹, Siddhartha G Jena¹, Hani Singer¹, Julia C Paoli¹, Ryan T Kim¹, Emil Kriukov², Sarah E Wilson¹, Renzhi Hou³, Aaron M Savage¹, Victor Cat¹, Louis V Cammarata⁴, S Y Celeste Wu¹, Vivien Bothe⁵, Burcu Erdogan¹, Shifa Hossain¹, Noah Lopez¹, Julia Losner¹, Juan Velazquez Matos¹, Sangwon Min¹, Sebastian Böhm¹, Anthony E Striker¹, Kelly E Dooling¹, Adam H Freedman⁶, Bobby Groves¹, Benjamin Tajer¹, Glory Kalu¹, Eric Wynn¹, Alan Y L Wong¹, Nadia Fröbisch⁵, Petr Baranov², Maksim V Plikus⁷, Jason D Buenrostro⁸, Brian J Haas⁹, Isaac M Chiu¹⁰, Timothy B Sackton⁶, Jessica L Whited¹¹

Affiliations

¹ Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138, USA.
² Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA 02114, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
³ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA.
⁴ Department of Statistics, Harvard University, Cambridge, MA 02138, USA.
⁵ Museum für Naturkunde Berlin, Berlin, Germany.
⁶ Informatics Group, Harvard University, 38 Oxford St., Cambridge, MA 02138, USA.
⁷ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
⁸ Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
⁹ The Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
¹⁰ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: jessica_whited@harvard.edu.

PMID: 41138727
DOI: 10.1016/j.cell.2025.09.025

Free article

Adrenergic signaling coordinates distant and local responses to amputation in axolotl

Duygu Payzin-Dogru et al. Cell. 2025.

Free article

. 2025 Oct 24:S0092-8674(25)01125-0.

doi: 10.1016/j.cell.2025.09.025. Online ahead of print.

Authors

Affiliations

¹ Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138, USA.
² Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA 02114, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
³ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA.
⁴ Department of Statistics, Harvard University, Cambridge, MA 02138, USA.
⁵ Museum für Naturkunde Berlin, Berlin, Germany.
⁶ Informatics Group, Harvard University, 38 Oxford St., Cambridge, MA 02138, USA.
⁷ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
⁸ Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
⁹ The Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
¹⁰ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: jessica_whited@harvard.edu.

PMID: 41138727
DOI: 10.1016/j.cell.2025.09.025

Abstract

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_2Α-adrenergic receptor, and local regeneration responses via β-adrenergic receptors. Both α_2A- and β-adrenergic signaling act upstream of mTOR signaling. Notably, systemically activated axolotls regenerate limbs faster than naive 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.

Keywords: amputation; limb; mTOR; noradrenaline; norepinephrine; peripheral nervous system; progenitor cells; regeneration; stem cells; systemic responses.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests J.L.W. is a co-founder of Animate Biosciences. I.M.C. consults for GSK Pharmaceuticals, and his lab has received sponsored research from Moderna and AbbVie/Allergan. J.D.B. holds patents related to ATAC-seq, consults for the Treehouse Family Foundation and is a scientific advisory board member of Camp4 and seqWell. M.V.P. is a co-founder of Amplifica Holdings Group and consults for L’Oreal and ODDITY, and his lab has received sponsored research from L’Oreal and AbbVie/Allergan.

Update of

Adrenergic signaling coordinates distant and local responses to amputation in axolotl.
Payzin-Dogru D, Froitzheim T, Blair SJ, Jena SG, Singer H, Paoli JC, Kim RT, Kriukov E, Wilson SE, Hou R, Savage AM, Cat V, Cammarata LV, Wu SYC, Bothe V, Erdogan B, Hossain S, Lopez N, Losner J, Matos JV, Min S, Böhm S, Striker AE, Dooling KE, Freedman AH, Groves B, Tajer B, Kalu G, Wynn E, Wong AYL, Fröbisch N, Baranov P, Plikus MV, Buenrostro JD, Haas BJ, Chiu IM, Sackton TB, Whited JL. Payzin-Dogru D, et al. bioRxiv [Preprint]. 2025 Jul 24:2021.12.29.474455. doi: 10.1101/2021.12.29.474455. bioRxiv. 2025. Update in: Cell. 2025 Oct 24:S0092-8674(25)01125-0. doi: 10.1016/j.cell.2025.09.025. PMID: 40777403 Free PMC article. Updated. Preprint.

LinkOut - more resources

Full Text Sources
- Elsevier Science
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Adrenergic signaling coordinates distant and local responses to amputation in axolotl

Affiliations

Adrenergic signaling coordinates distant and local responses to amputation in axolotl

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

LinkOut - more resources

Full Text Sources

Miscellaneous