缺氧条件下神经干细胞/祖细胞在发育过程中通过自分泌VEGF-A组织自身优势生态位。

IF 5 3区 医学 Q2 IMMUNOLOGY Inflammation and Regeneration Pub Date : 2023-02-01 DOI:10.1186/s41232-022-00254-2
Taichi Kashiwagi, Yuuki Takazawa, Tetsushi Kagawa, Tetsuya Taga
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摘要

背景:组织干细胞被限制在一个称为生态位的特殊微环境中。在这样的生态位中,干细胞被提供营养,并与其他细胞接触,以保持其特性,并保持或扩大其种群规模。此外,氧浓度是干细胞生态位的关键因素。已知成体神经干细胞/祖细胞(NSPCs)存在于缺氧生态位中。胎儿器官(包括大脑)的氧浓度水平低于母体器官。然而,胎儿NSPCs如何适应大脑发育过程中的缺氧环境,特别是在脑膜和脑室周围血管开始侵入端脑之前,还没有完全阐明。方法:从胚胎日(E) 11.5或E14.5小鼠胚胎的大脑皮层制备NSPCs,用FGF2孵育4 d富集。为了评估NSPC的数量,进行了神经球形成试验。在低氧(1% O2)或常氧条件下培养稀疏的NSPCs形成神经球。ELISA法检测NSPCs在培养基中分泌的VEGF-A。采用原位杂交和免疫组织化学方法研究VEGF-A和Hif-1a在发育中的表达。结果:与正常缺氧相比,低氧条件下胚胎NSPCs的神经球形成明显增加。缺氧条件下NSPCs中Vegf-A基因表达和蛋白分泌均上调。重组VEGF-A或缺氧NSPC培养的条件培养基均增强了常氧NSPC的神经球形成能力,VEGF-A信号抑制剂减弱了神经球形成能力。此外,在发育中的大脑中,VEGF-A在NSPCs被限制的VZ中强烈表达。结论:我们发现NSPCs以自分泌方式分泌VEGF-A,以有效地维持自身在缺氧发育环境下的生存。我们的研究结果表明,在血管系统不成熟时,NSPCs具有适应缺氧的潜力,可以组织涉及VEGF-A的自我优势生态位。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Organization of self-advantageous niche by neural stem/progenitor cells during development via autocrine VEGF-A under hypoxia.

Background: Tissue stem cells are confined within a special microenvironment called niche. Stem cells in such a niche are supplied with nutrients and contacted by other cells to maintain their characters and also to keep or expand their population size. Besides, oxygen concentration is a key factor for stem cell niche. Adult neural stem/progenitor cells (NSPCs) are known to reside in a hypoxic niche. Oxygen concentration levels are lower in fetal organs including brain than maternal organs. However, how fetal NSPCs adapt to the hypoxic environment during brain development, particularly before pial and periventricular vessels start to invade the telencephalon, has not fully been elucidated.

Methods: NSPCs were prepared from cerebral cortices of embryonic day (E) 11.5 or E14.5 mouse embryos and were enriched by 4-day incubation with FGF2. To evaluate NSPC numbers, neurosphere formation assay was performed. Sparsely plated NSPCs were cultured to form neurospheres under the hypoxic (1% O2) or normoxic condition. VEGF-A secreted from NSPCs in the culture medium was measured by ELISA. VEGF-A expression and Hif-1a in the developing brain was investigated by in situ hybridization and immunohistochemistry.

Results: Here we show that neurosphere formation of embryonic NSPCs is dramatically increased under hypoxia compared to normoxia. Vegf-A gene expression and its protein secretion were both up-regulated in the NSPCs under hypoxia. Either recombinant VEGF-A or conditioned medium of the hypoxic NSPC culture enhanced the neurosphere forming ability of normoxic NSPCs, which was attenuated by a VEGF-A signaling inhibitor. Furthermore, in the developing brain, VEGF-A was strongly expressed in the VZ where NSPCs are confined.

Conclusions: We show that NSPCs secret VEGF-A in an autocrine fashion to efficiently maintain themselves under hypoxic developmental environment. Our results suggest that NSPCs have adaptive potential to respond to hypoxia to organize self-advantageous niche involving VEGF-A when the vascular system is immature.

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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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