Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration

• 成果类型: Article
• 署名作者: Tsissios, Georgios; Leleu, Marion; Hu, Kelly; Demirtas, Alp Eren; Hu, Hanrong; Vinzens, Sabrina; Kawanishi, Toru; Skoufa, Evangelia; Valanju, Atharva; Valente, Alessandro; Noseda, Lorenzo; Ochi, Haruki; Herrera, Antonio; Sakar, Selman; Tanaka, Mikiko; Wickstrom, Sara A.; Zenk, Fides; Aztekin, Can
• 署名单位: Swiss Federal Institutes of Technology Domain; Swiss School of Public Health (SSPH+); Ecole Polytechnique Federale de Lausanne; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Max Planck Society; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Kobe University; Kobe University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adw8526
• 发表日期: 2026-04-09
• 页码: eadw8526
• 关键词: hypoxia-inducible factor; hippo signaling pathway; XENOPUS LIMB; REGULATES YAP; expression; GROWTH; cells; dedifferentiation; determinant; epithelium

摘要

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 laevis tadpole limbs. Lowering environmental oxygen or stabilizing the oxygen-sensitive hypoxia-inducible factor 1A (HIF1A) induced rapid wound healing in mouse limbs. This response was accompanied by altered cellular mechanics, metabolism, and a histone landscape that primed regenerative cell states. Conversely, Xenopus tadpole limbs retained these features even under high oxygen levels. Their reduced oxygen-sensing capacity was associated with decreased HIF1A-regulating gene expression. Our results thus identify species-specific oxygen-sensing capacity as a fundamental, targetable mechanism that can unlock latent regenerative programs in mammals.