Secretome of brain microvascular endothelial cells promotes endothelial barrier tightness and protects against hypoxia-induced vascular leakage.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Medicine Pub Date : 2024-08-26 DOI:10.1186/s10020-024-00897-6
Rodrigo Azevedo Loiola, Johan Hachani, Sophie Duban-Deweer, Emmanuel Sevin, Paulina Bugno, Agnieszka Kowalska, Eleonora Rizzi, Fumitaka Shimizu, Takashi Kanda, Caroline Mysiorek, Maciej Mazurek, Fabien Gosselet
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Abstract

Cell-based therapeutic strategies have been proposed as an alternative for brain and blood vessels repair after stroke, but their clinical application is hampered by potential adverse effects. We therefore tested the hypothesis that secretome of these cells might be used instead to still focus on cell-based therapeutic strategies. We therefore characterized the composition and the effect of the secretome of brain microvascular endothelial cells (BMECs) on primary in vitro human models of angiogenesis and vascular barrier. Two different secretome batches produced in high scale (scHSP) were analysed by mass spectrometry. Human primary CD34+-derived endothelial cells (CD34+-ECs) were used as well as in vitro models of EC monolayer (CMECs) and blood-brain barrier (BBB). Cells were also exposed to oxygen-glucose deprivation (OGD) conditions and treated with scHSP during reoxygenation. Protein yield and composition of scHSP batches showed good reproducibility. scHSP increased CD34+-EC proliferation, tubulogenesis, and migration. Proteomic analysis of scHSP revealed the presence of growth factors and proteins modulating cell metabolism and inflammatory pathways. scHSP improved the integrity of CMECs, and upregulated the expression of junctional proteins. Such effects were mediated through the activation of the interferon pathway and downregulation of Wnt signalling. Furthermore, OGD altered the permeability of both CMECs and BBB, while scHSP prevented the OGD-induced vascular leakage in both models. These effects were mediated through upregulation of junctional proteins and regulation of MAPK/VEGFR2. Finally, our results highlight the possibility of using secretome from BMECs as a therapeutic alternative to promote brain angiogenesis and to protect from ischemia-induced vascular leakage.

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脑微血管内皮细胞的分泌物促进内皮屏障的紧密性,防止缺氧引起的血管渗漏。
以细胞为基础的治疗策略已被提出作为中风后脑部和血管修复的替代方法,但其临床应用受到潜在不良影响的阻碍。因此,我们测试了一个假设,即这些细胞的分泌物组可能会被用于替代仍以细胞为基础的治疗策略。因此,我们研究了脑微血管内皮细胞(BMECs)分泌物的组成及其对原代体外人体血管生成和血管屏障模型的影响。质谱分析了两种不同批次的大规模生产的分泌物组(scHSP)。使用了人类原代 CD34+ 衍生内皮细胞(CD34+-ECs)以及 EC 单层(CMECs)和血脑屏障(BBB)体外模型。细胞还暴露于氧气-葡萄糖剥夺(OGD)条件下,并在复氧过程中接受 scHSP 处理。scHSP 增加了 CD34+-EC 的增殖、肾小管生成和迁移。scHSP的蛋白质组分析表明存在生长因子和调节细胞新陈代谢和炎症通路的蛋白质。scHSP改善了CMEC的完整性,并上调了连接蛋白的表达。这些作用是通过激活干扰素通路和下调 Wnt 信号传导介导的。此外,OGD 改变了 CMECs 和 BBB 的通透性,而 scHSP 在这两种模型中都能防止 OGD 引起的血管渗漏。这些效应是通过上调连接蛋白和调节 MAPK/VEGFR2 介导的。最后,我们的研究结果凸显了利用 BMECs 分泌物作为促进脑血管生成和防止缺血诱导的血管渗漏的替代疗法的可能性。
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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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