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神经祖细胞中Wnt/β-连环蛋白的激活调节血脑屏障发育并促进神经炎症。

Activation of Wnt/β-catenin in neural progenitor cells regulates blood-brain barrier development and promotes neuroinflammation.

作者信息

Sebo Dylan J, Ali Irshad, Fetsko Audrey R, Trimbach Aubrey A, Taylor Michael R

机构信息

School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA.

出版信息

Sci Rep. 2025 Jan 28;15(1):3496. doi: 10.1038/s41598-025-85784-8.

DOI:10.1038/s41598-025-85784-8
PMID:39875426
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11775206/
Abstract

The central nervous system (CNS) requires specialized blood vessels to support neural function within specific microenvironments. During neurovascular development, endothelial Wnt/β-catenin signaling is required for BBB development within the brain parenchyma, whereas fenestrated blood vessels that lack BBB properties do not require Wnt/β-catenin signaling. Here, we used zebrafish to further characterize this phenotypic heterogeneity of the CNS vasculature. Using transgenic reporters of Wnt/β-catenin transcriptional activity, we found an inverse correlation between activated Wnt/β-catenin signaling in endothelial cells (ECs) versus non-ECs within these distinct microenvironments. Our results indicated that the level of Wnt/β-catenin signaling in non-ECs may regulate Wnt/β-catenin activity in adjacent ECs. To further test this concept, we generated a transgenic Tet-On inducible system to drive constitutively active β-catenin expression in neural progenitor cells (NPCs). We found that dose-dependent activation of Wnt/β-catenin in NPCs caused severe deficiency in CNS angiogenesis and BBB development. Additionally, we discovered a significant increase in the proliferation of microglia and infiltration of peripheral neutrophils indicative of a stereotypical neuroinflammatory response. In conclusion, our results demonstrate the importance of proper Wnt/β-catenin signaling within specific CNS microenvironments and highlights the potentially deleterious consequences of aberrant Wnt activation.

摘要

中枢神经系统（CNS）需要特殊的血管来支持特定微环境中的神经功能。在神经血管发育过程中，内皮细胞的Wnt/β-连环蛋白信号传导是脑实质内血脑屏障（BBB）发育所必需的，而缺乏BBB特性的有孔血管则不需要Wnt/β-连环蛋白信号传导。在这里，我们利用斑马鱼进一步表征中枢神经系统血管系统的这种表型异质性。使用Wnt/β-连环蛋白转录活性的转基因报告基因，我们发现在这些不同的微环境中，内皮细胞（ECs）与非内皮细胞中激活的Wnt/β-连环蛋白信号之间呈负相关。我们的结果表明，非内皮细胞中Wnt/β-连环蛋白信号的水平可能调节相邻内皮细胞中Wnt/β-连环蛋白的活性。为了进一步验证这一概念，我们构建了一个转基因Tet-On诱导系统，以驱动神经祖细胞（NPCs）中组成型活性β-连环蛋白的表达。我们发现，NPCs中Wnt/β-连环蛋白的剂量依赖性激活导致中枢神经系统血管生成和血脑屏障发育严重缺陷。此外，我们发现小胶质细胞增殖和外周中性粒细胞浸润显著增加，这表明存在典型的神经炎症反应。总之，我们的结果证明了特定中枢神经系统微环境中适当的Wnt/β-连环蛋白信号传导的重要性，并突出了异常Wnt激活的潜在有害后果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/fc5de6f7ee7d/41598_2025_85784_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/68771aab44d8/41598_2025_85784_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/2568e6cfea00/41598_2025_85784_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/fc5de6f7ee7d/41598_2025_85784_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/68771aab44d8/41598_2025_85784_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/5213abd4ab88/41598_2025_85784_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/12d20da3f15b/41598_2025_85784_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/2568e6cfea00/41598_2025_85784_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d200/11775206/fc5de6f7ee7d/41598_2025_85784_Fig7_HTML.jpg

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