Savage Aaron M, Wagner Alexandra C, Kim Ryan T, Gilbert Paul, Singer Hani D, Chen Erica, Kim Elane M, Lopez Noah, Dooling Kelly E, Paoli Julia C, Wu S Y Celeste, Böhm Sebastian, Froitzheim Tim, Chilambi Rachna, Blair Steven J, Powell Connor J, Abouelela Adnan, Luong Anna G, Thornton Kara N, Harake Noora, Karabacak Alparslan, Tajer Benjamin, Payzin-Dogru Duygu, Whited Jessica L
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA; The Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Dev Biol. 2025 Sep;525:206-215. doi: 10.1016/j.ydbio.2025.05.030. Epub 2025 Jun 5.
Salamanders are capable of regenerating whole limbs throughout life, a feat that is unmatched by other tetrapods. Limb regeneration is dependent upon the formation of a blastema containing progenitor cells which give rise to most tissues of the regenerated limb. Many signaling pathways, including FGF, BMP and Wnt, are required for regeneration, but the role of VEGF signaling during salamander limb regeneration is not well understood, particularly outside of angiogenesis. Here we show that VEGF signaling is essential for limb regeneration and that blastema cells and limb fibroblasts display impaired proliferation in the absence of VEGF signaling. Loss of VEGF signaling reduces expression of EMT-associated genes, suggesting VEGF signaling promotes expression of EMT-associated transcription factors, including Snai2, during axolotl limb regeneration. These findings highlight potential roles for VEGF signaling during regeneration which may extend beyond its expected pro-angiogenic function.
蝾螈一生都能够再生整个肢体，这一能力是其他四足动物所无法比拟的。肢体再生依赖于芽基的形成，芽基中含有祖细胞，这些祖细胞可分化为再生肢体的大部分组织。包括FGF、BMP和Wnt在内的许多信号通路都参与再生过程，但VEGF信号通路在蝾螈肢体再生过程中的作用尚未完全明确，尤其是在血管生成之外的作用。在此我们表明，VEGF信号通路对肢体再生至关重要，并且在缺乏VEGF信号时，芽基细胞和肢体成纤维细胞的增殖会受损。VEGF信号的缺失会降低EMT相关基因的表达，这表明在蝾螈肢体再生过程中，VEGF信号通路可促进包括Snai2在内的EMT相关转录因子的表达。这些发现凸显了VEGF信号通路在再生过程中可能发挥的潜在作用，其作用可能超出了预期的促血管生成功能。
