中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (10): 2938-2954.doi: 10.4103/NRR.NRR-D-23-01881

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

端脑刺伤诱导斑马鱼再生血管生成和神经发生:揭示血管内皮生长因子信号和小胶质细胞的作用

  

  • 出版日期:2025-10-15 发布日期:2025-02-09

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish: unveiling the role of vascular endothelial growth factor signaling and microglia

Danielle Fernezelian, Philippe Rondeau, Laura Gence, Nicolas Diotel*   

  1. Université de La Réunion, INSERM, UMR 1188, Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint Pierre, La Réunion, France
  • Online:2025-10-15 Published:2025-02-09
  • Contact: Nicolas Diotel, PhD, nicolas.diotel@univ-reunion.fr.
  • Supported by:
    This work was supported by European Regional Development Funds RE0022527 ZEBRATOX (EU-Région Réunion-French State national counterpart; to Nicolas Diotel and Jean-Loup Bascands).

摘要:

哺乳动物脑损伤后,再生血管生成和神经发生被证明是同时发生的,这表明这两个过程之间存在密切联系。然而,人们对这两个过程的相互作用机制还不甚了解。此项研究旨在分析端斑马鱼脑刺伤后血管生成和神经发生之间的相关性。首先,实验利用可分别观察血管和小胶质细胞的 Tg(fli1:EGFP × mpeg1.1:mCherry)斑马鱼品系,分析了损伤后 1-21 天(dpl)的再生血管生成情况。与此同时,实验还利用免疫组化技术检测了斑马鱼脑室区神经源龛中脑细胞的增殖情况。结果发现,斑马鱼脑损伤后,血管面积和宽度以及fli1转基因和血管内皮生长因子(vegfaa和vegfbb)的表达均有所增加。与此同时,神经干细胞的增殖也所有增加,在3至5 dpl之间达到高峰,其方式与血管生成类似,同时伴随着小胶质细胞募集。然后,实验通过在病变部位注射抗血管生成药物(Tivozanib)或Vegf证明了阻断或激活Vegf信号可调节血管生成和神经源过程以及小胶质细胞的募集。最后,实验证明了通过注射含氯膦酸脂质体或地塞米松抑制了小胶质细胞会损害再生神经发生以及损伤诱导的血管生成。总之,实验描述了斑马鱼的再生血管生成,并强调了炎症在这一过程中的作用。此外,还证明了血管生成和神经发生都参与了大脑修复,而由 Vegf 信号激活的小胶质细胞和炎症依赖机制是这些过程的重要促成因素。这项研究为更好地了解 Vegf 对小胶质细胞的影响以及旨在促进血管生成以改善脑损伤后大脑可塑性的研究铺平了道路。

https://orcid.org/0000-0003-2032-518X (Nicolas Diotel)

Abstract: After brain damage, regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals, suggesting a close link between these processes. However, the mechanisms by which these processes interact are not well understood. In this work, we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury. To this end, we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms. First, using the Tg(fli1:EGFP × mpeg1.1:mCherry) zebrafish line, which enables visualization of blood vessels and microglia respectively, we analyzed regenerative angiogenesis from 1 to 21 days post-lesion. In parallel, we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry. We found that after brain damage, the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor (vegfaa and vegfbb) were increased. At the same time, neural stem cell proliferation was also increased, peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis, along with the recruitment of microglia. Then, through pharmacological manipulation by injecting an antiangiogenic drug (Tivozanib) or Vegf at the lesion site, we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes, as well as microglial recruitment. Finally, we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis, as previously described, as well as injury-induced angiogenesis. In conclusion, we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process. In addition, we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes. This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Key words: angiogenesis,  cerebral damage,  inflammation,  neurogenesis,  stab wound,  telencephalon,  vascular endothelial growth factor,  zebrafish