Ling Yu, Mingquan Yan, Jennifer Simkin, Paulina D Ketcham, Eric Leininger, Manjong Han, Ken Muneoka
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引用次数: 35
摘要
再生小鼠指尖是研究哺乳动物胚泡形成和表胚再生的独特模型。胚部是典型的无血管的,我们之前报道过一个已知的抗血管生成因子基因Pedf的表达与成功的再生反应相关(Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K.(2010))。BMP信号诱导新生小鼠手指再生。发展,137,551-559)。在这里,我们发现在再生过程中,Vegfa转录本在胚芽中没有被检测到,但在分化开始时表达。应用血管内皮生长因子治疗截肢创面可促进血管生成,但抑制血管再生。接下来,我们测试了骨形态发生蛋白9 (BMP9),这是另一种已知的血管生成介质,发现BMP9也是指尖再生的有效抑制剂。BMP9诱导手指残端Vegfa表达,表明再生失败是通过增强血管生成介导的。最后,我们发现BMP9对再生的抑制可以通过色素上皮衍生因子治疗完全恢复。这些研究表明,过早的血管生成抑制再生,并提供令人信服的证据表明,血管生成的调节是设计旨在刺激哺乳动物再生的治疗方法的关键因素。
Angiogenesis is inhibitory for mammalian digit regeneration.
The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti-angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551-559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium-derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration.