Amazing stuff! Be aware, there are two concurrent studies published on this subject. I ignored the second study.
"... For decades, biologists have tried to understand why. Now a team ... has 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 whether regeneration can even begin. ...
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.
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. ..."
From the abstract of the Perspective:
"The ability to regenerate varies widely across the animal kingdom.
Planarians, a type of flatworm, can rebuild their entire body from small fragments.
Fish and salamanders can regenerate complex structures such as fins and limbs.
By contrast, mammals exhibit much more limited natural regenerative abilities (2). This disparity has profound clinical consequences. Poor wound healing, scarring, and limb loss continue to diminish quality of life. Defining how animals orchestrate regenerative processes is important for developing therapies for humans. Emerging evidence suggests that the genes carried by mammals may not render them intrinsically regeneration incompetent.
Instead, the default mammalian wound environment may reinforce nonregenerative programs. On pages 177 and 176 of this issue, Mui et al. (11) and Tsissios et al. (12), respectively, report that regeneration is not simply a fixed genetic trait but rather a state that is dependent on the extracellular environment, oxygen sensing, and epigenetics."
From the editor's summary and abstract:
"Editor’s summary
Some vertebrates can regenerate limbs, whereas others cannot. By comparing regenerating frog tadpoles and nonregenerating mouse embryonic limbs,
Tsissios et al. found that species-specific oxygen sensing determines whether amputation triggers limb regeneration ...
Frog tadpoles exhibited reduced oxygen sensing associated with diminished regulation of hypoxia-inducible factor 1A (HIF1A), enabling robust regeneration by promoting biomechanical, epigenetic, and metabolic states conducive to tissue regrowth.
By contrast, mouse limbs displayed heightened sensitivity to oxygen, which destabilizes HIF1A and prevents regeneration. Lowering environmental oxygen levels or stabilizing HIF1A allowed mouse limbs to initiate regeneration.
Mui et al. used a mouse digit amputation model to investigate why some injuries regenerate while others scar. They found that the extracellular matrix, the network of proteins and sugars surrounding cells, was crucial to regeneration. Regenerating tissue is soft, fluid, and rich in hyaluronic acid, whereas nonregenerating tissue is stiff and collagen heavy.
Depleting hyaluronic acid halted regeneration and triggered scarring, whereas stabilizing it improved bone regrowth.
Structured Abstract
INTRODUCTION
Some vertebrates, such as frog tadpoles and salamanders, can regenerate lost limbs after amputation, whereas mammals cannot. Many regeneration-associated molecular pathways and cellular programs are conserved across species, suggesting a possible latent limb-regenerative capacity for mammals. Nonetheless, it remains unclear why these pathways and cell types are not activated after limb amputation and whether limb regenerative programs can, in principle, be initiated in mammals.
RATIONALE
Direct functional comparisons of amputation responses across species are difficult in vivo because of physiological, environmental, and developmental differences, as well as practical constraints. We therefore used limb explants, tissues grown outside the body, as a highly controlled experimental platform.
Having shown that frog tadpole (Xenopus laevis) limbs initiate regeneration as explants, we investigated whether embryonic mouse (Mus musculus) limbs do so under comparable conditions and, if not, which mechanisms distinguish regenerative from nonregenerative species.
RESULTS
We found that subatmospheric oxygen conditions, or stabilization of the oxygen-sensitive transcription factor hypoxia-inducible factor 1A (HIF1A), promote rapid wound healing after amputation in embryonic mouse limbs.
Reduced oxygen availability reshaped cellular biomechanical properties associated with YAP activation and metabolic states, particularly glycolysis. In parallel, it also rewired the chromatin landscape by decreasing the repressive histone mark H3K27me3 and increasing the activating mark H3K4me3, thereby permitting regenerative gene expression and the formation of limb regeneration–associated cell types.
By contrast, atmospheric oxygen conditions impaired these processes in mouse limbs. In addition, frog tadpole limbs displayed robust wound healing, regenerative cell-type formation, and stable biomechanical, epigenetic, and metabolic features across a wide range of oxygen conditions, even those greatly exceeding atmospheric oxygen levels.
This reduced oxygen sensing was associated with lower expression of HIF1A regulators, resulting in stable HIF1A activity relative to mice. Extending this analysis, we found that regenerative axolotls also show lower expression of HIF1A regulators, whereas humans exhibit a heightened oxygen-sensing signature similar to mice.
CONCLUSION
We propose species-specific oxygen-sensing capacity as a key determinant of limb regeneration initiation across vertebrates. Reduced oxygen sensing promotes biomechanical, epigenetic, and metabolic programs that are conducive to regeneration, with implications extending to development, disease, evolution, and cross-species comparisons.
Finally, our findings demonstrate that modulation of oxygen-sensing pathways can unlock latent limb-regenerative programs in mammals, providing a mechanistic route toward inducing limb regeneration in adult mammals."
Awakening latent regeneration in mammals (Perspective, no public access)
Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration (no public access)
Hyaluronic acid and tissue mechanics orchestrate mammalian digit tip regeneration (no public access)
Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration.
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