One of the major projects within the study of comparative biology is the attempt to understand why adult individuals of some species can fully regenerate lost tissues following injury, while mammals such as our own species cannot. A variety of modest inroads into identifying potentially important differences in cellular biochemistry and activity have been made, such as work focused on senescent cells and macrophages, but it remains an unsolved challenge. Researchers here present more data to add to that already under consideration, focused on the role of oxygen sensing in the initial response to injury. It is unclear as to whether it can lead to dramatic improvements in mammalian regeneration, but the work suggests that regeneration could be improved via manipulation of oxygen sensing in injured tissues.
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.
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.
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. 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. 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.
Link: https://www.tuebingen.mpg.de/280592/news_publication_26212730_transferred
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