B-T.26: Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration.
Why mammals cannot regenerate limbs like amphibians do presents a long‑standing puzzle in biology. To uncover the underlying differences, we compared amputation responses of embryonic mouse (Mus musculus) and Xenopus laevistadpole limbs. Lowering environmental oxygen or stabilizing the oxygen‑sensitive hypoxia‑inducible factor 1A (HIF1A) induced rapid wound healing in mouse limbs, accompanied by altered cellular mechanics, metabolism, and a histone landscape that primed regenerative cell states. Comparative transcriptomic and epigenomic analyses revealed a conserved, amphibian‑like features enriched for wound‑healing, histone modifications, and metabolic functions, activated under low oxygen conditions in mouse. Conversely, Xenopus tadpole limbs retained these features even under high oxygen levels; their reduced oxygen‑sensing capacity was associated with decreased expression of HIF1A‑regulating genes, as identified through cross‑species transcriptomic profiles. Our results thus propose species‑specific oxygen‑sensing capacity as a fundamental, targetable mechanism that can unlock latent regenerative programs in mammals. By integrating multi‑species scRNA‑seq, time‑resolved scMultiomics, and epigenomic profiling, we provide a bioinformatically informed, genome‑scale framework linking oxygen sensing to the activation of regenerative cell states in across vertebrates.
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