近日，德国慕尼黑大学Dominik Paquet及其团队的最新研究提出了一个完全iPS细胞衍生的人类血脑屏障3D模型，用于探索神经血管疾病机制和治疗干预。该研究于2025年12月15日发表于国际一流学术期刊《自然—神经科学》杂志上。

在这里，课题组研究人员报道了一个完全人类诱导多能干细胞（iPS）衍生的，由内皮细胞（ECs），壁细胞和星形胶质细胞组成的微流体三维（3D）血脑屏障模型。他们的模型表达了典型的命运标记，在血管状管道中形成屏障，并实现了包括人类血液在内的完美结合。在ECs中，FOXF2是脑血管疾病的主要风险基因，其缺失可诱导血脑屏障功能障碍的关键特征，包括细胞连接完整性受损和小泡形成增强。蛋白质组学分析显示胞吞作用和细胞连接途径失调。在EC特异性Foxf2缺乏症小鼠中所见的疾病特征与表型相似。

此外，基于脂质纳米颗粒的Foxf2 mRNA治疗可挽救血脑屏障缺陷，显示出药物开发的潜力。

据悉，血脑屏障（BBB）的完整性对大脑稳态至关重要，其功能障碍会导致神经血管和神经退行性疾病。关于血脑屏障功能的机制研究主要是在啮齿动物和体外模型中进行的，这些模型概括了一些疾病特征，但对人类的可转译性有限，并对药物发现构成挑战。

附：英文原文

Title: A fully iPS-cell-derived 3D model of the human blood–brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions

Author: Gonzlez-Gallego, Judit, Todorov-Vlgyi, Katalin, Mller, Stephan A., Antesberger, Sophie, Todorov, Mihail Ivilinov, Malik, Rainer, Grimalt-Mirada, Rita, Gonalves, Carolina Cardoso, Schifferer, Martina, Kislinger, Georg, Weisheit, Isabel, Lindner, Barbara, Crusius, Dennis, Kroeger, Joseph, Borri, Mila, Erturk, Ali, Nelson, Mark, Misgeld, Thomas, Lichtenthaler, Stefan F., Dichgans, Martin, Paquet, Dominik

Issue&Volume: 2025-12-15

Abstract: Blood–brain barrier (BBB) integrity is critical for brain homeostasis, with malfunctions contributing to neurovascular and neurodegenerative disorders. Mechanistic studies on BBB function have been mostly conducted in rodent and in vitro models, which recapitulate some disease features, but have limited translatability to humans and pose challenges for drug discovery. Here we report on a fully human induced pluripotent stem (iPS)-cell-derived, microfluidic three-dimensional (3D) BBB model consisting of endothelial cells (ECs), mural cells and astrocytes. Our model expresses typical fate markers, forms a barrier in vessel-like tubes and enables perfusion, including with human blood. Deletion of FOXF2 in ECs, a major risk gene for cerebral small vessel disease, induced key features of BBB dysfunction, including compromised cell junction integrity and enhanced caveolae formation. Proteomic analysis revealed dysregulated endocytosis and cell junction pathways. Disease features phenocopied those seen in mice with EC-specific Foxf2 deficiency. Moreover, lipid-nanoparticle-based treatment with Foxf2 mRNA rescued BBB deficits, demonstrating the potential for drug development.

DOI: 10.1038/s41593-025-02123-w

Source: https://www.nature.com/articles/s41593-025-02123-w