When oxygen determines if a limb can regrow

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Researchers at EPFL have discovered how oxygen-sensing explains why amphibians regenerate limbs and mammals do not.

Imagen by Amel Uzunovic on Pexels

Some animals can regrow lost body parts. Salamanders and frog tadpoles can rebuild entire limbs after amputation. Mammals cannot. For decades, biologists have tried to understand why.

Limb regeneration begins with wound healing. After amputation, cells at the injury site must rapidly seal the wound and switch into regenerative cell types. In amphibians, this process runs smoothly. In mammals, it stalls early. Wound closure is slow and scar formation takes over, blocking regeneration.

One key difference lies in the environment. Amphibian larvae develop in water, where oxygen levels are lower than in air. Moreover, many regeneration-competent species live in aquatic environments. Meanwhile, mammalian tissues are typically exposed to higher oxygen levels after injury.

What is unclear is whether this difference played a direct role in regeneration or was merely a consequence of lifestyle.

A team led by Can Aztekin** at **EPFL (now at the Friedrich Miescher Laboratory of the Max Planck Society) discovered that oxygen plays a crucial role in limb regeneration. By comparing amputated limbs from frog tadpoles and embryonic mice, the researchers found that the way cells sense oxygen determines if regeneration can even begin.

The study was published in Science.

A latent regenerative capacity
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“For a long time, regeneration research focused on amphibians, while mammalian regeneration was rarely examined experimentally side by side in a comparable manner,” Aztekin said. “Although many studies showed that regenerative species such as amphibians and mammals share similar genes, suggesting that mammals may retain a latent regenerative capacity, it remained unclear whether mammalian tissues can indeed activate limb regenerative programs, and what prevents them from doing so.”

The researchers amputated developing limbs from frog tadpoles and mouse embryos and cultured them outside the body under controlled oxygen conditions. Oxygen levels were lowered to match aquatic environments or raised to levels close to air.

They tracked how cells responded by measuring wound closure, cell movement, gene activity, metabolism, and epigenetic states, including changes to DNA packaging. The work focused on HIF1A, a protein that acts as a cellular oxygen sensor. When oxygen is low, HIF1A becomes stable and activates programs that set the stage for wound healing and regeneration.

A change in cell behavior
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Lowering oxygen levels had a clear effect on the limbs of mouse embryos. Under reduced oxygen, mouse cells closed wounds faster and showed signs of entering a regenerative program. Stabilizing HIF1A produced similar effects, even when oxygen levels remained high.

Low oxygen also changed cell behavior, with skin cells becoming more mobile and altering their mechanical properties. Metabolism shifted toward glycolysis, a process that takes place in low-oxygen states. At the same time, chemical marks on DNA-associated proteins shifted to favor the activation of regeneration-related genes.

Frog tadpoles behaved differently. Their limbs regenerated efficiently across a wide range of oxygen levels, including levels well above those normally found in air. Molecular analysis showed that their cells maintain stable HIF1A activity even when oxygen increases, due to low expression of genes that normally shut this pathway down.

By comparing frogs, axolotls, mice, and human datasets, the team found a consistent pattern. Regeneration-competent amphibians show reduced oxygen-sensing capacity, allowing regenerative programs to be initiated and sustained. Mammals show the opposite pattern. Their cells respond strongly to oxygen and switch regenerative programs off soon after injury.

A fresh perspective to centuries-old question
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The results suggest that mammalian limbs retain latent regenerative potential at early stages, depending on how cells respond to environmental signals such as oxygen. This means that adjusting oxygen-sensing pathways might one day improve wound healing or regenerative responses in humans.

Importantly, the findings demonstrate the activation of regenerative mechanisms in mammals, not the complete regrowth of a fully formed limb. But although the study does not claim that human limb regrowth is imminent, it does show that differences once thought to be fixed between species may instead hinge on how cells respond to their environment.

**“We are very excited about our findings,”**Aztekin said. “By directly comparing species that can and cannot regenerate, we bring a fresh perspective to a centuries-old question. Our results show that regenerative programs can be triggered in mammalian tissues and begin to outline a clear, testable path toward promoting limb regeneration in adult mammals.”

This experiment, conducted at EPFL under conditions governed by Swiss animal welfare legislation, was approved by the relevant veterinary authorities, notably because the potential knowledge gain was deemed to outweigh the potential suffering inflicted on the animal.

Citation
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The study Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration was published in Science magazine. Authors: Georgios Tsissios, Marion Leleu, Kelly Hu, Alp Eren Demirtas, Hanrong Hu, Sabrina Vinzens, Toru Kawanishi, Evangelia Skoufa, Atharva Valanju, Alessandro Valente, Lorenzo Noseda, Haruki Ochi, Antonio Herrera, Selman Sakar, Mikiko Tanaka, Sara A. Wickström, Fides Zenk, and Can Aztekin

Science 9 Apr 2026 Vol 392, Issue 6794 DOI: 10.1126/science.adw8526

Other contributors
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EPFL NeuroNA Chair in Epigenomics of Neurodevelopmental disorders (EpiGN)
EPFL Bioinformatics Competence Center
Max Planck Institute for Molecular Biomedicine
Institute of Science Tokyo
EPFL Institute of Bioengineering
Kobe University

Funding
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Max Planck Society

-Friedrich Miescher Laboratory of the Max Planck Society

-EPFL ELISIR

Gabriella Giorgi-Cavaglieri Foundation
Swiss National Science Foundation
Branco Weiss Fellowship
Novartis Foundation
Swiss 3R Competence Center

References
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Georgios Tsissios, Marion Leleu, Kelly Hu, Alp Eren Demirtas, Hanrong Hu, Sabrina Vinzens, Toru Kawanishi, Evangelia Skoufa, Atharva Valanju, Alessandro Valente, Lorenzo Noseda, Haruki Ochi, Antonio Herrera, Selman Sakar, Mikiko Tanaka, Sara A. Wickström, Fides Zenk, Can Aztekin. Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration. Science 09 April 2026. DOI: 10.1126/science.adw8526

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