Potjewyd Geoffrey, Kellett Katherine A B, Hooper Nigel M
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K.
Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and University of Manchester, Manchester, U.K.
Neuronal Signal. 2021 Nov 9;5(4):NS20210027. doi: 10.1042/NS20210027. eCollection 2021 Dec.
The neurovascular unit (NVU), consisting of neurons, glial cells, vascular cells (endothelial cells, pericytes and vascular smooth muscle cells (VSMCs)) together with the surrounding extracellular matrix (ECM), is an important interface between the peripheral blood and the brain parenchyma. Disruption of the NVU impacts on blood-brain barrier (BBB) regulation and underlies the development and pathology of multiple neurological disorders, including stroke and Alzheimer's disease (AD). The ability to differentiate induced pluripotent stem cells (iPSCs) into the different cell types of the NVU and incorporate them into physical models provides a reverse engineering approach to generate human NVU models to study BBB function. To recapitulate the situation such NVU models must also incorporate the ECM to provide a 3D environment with appropriate mechanical and biochemical cues for the cells of the NVU. In this review, we provide an overview of the cells of the NVU and the surrounding ECM, before discussing the characteristics (stiffness, functionality and porosity) required of hydrogels to mimic the ECM when incorporated into NVU models. We summarise the approaches available to measure BBB functionality and present the techniques in use to develop robust and translatable models of the NVU, including transwell models, hydrogel models, 3D-bioprinting, microfluidic models and organoids. The incorporation of iPSCs either without or with disease-specific genetic mutations into these NVU models provides a platform in which to study normal and disease mechanisms, test BBB permeability to drugs, screen for new therapeutic targets and drugs or to design cell-based therapies.
神经血管单元（NVU）由神经元、神经胶质细胞、血管细胞（内皮细胞、周细胞和血管平滑肌细胞（VSMC））以及周围的细胞外基质（ECM）组成，是外周血与脑实质之间的重要界面。NVU的破坏会影响血脑屏障（BBB）的调节，并构成包括中风和阿尔茨海默病（AD）在内的多种神经系统疾病发生和病理的基础。将诱导多能干细胞（iPSC）分化为NVU的不同细胞类型并将它们整合到物理模型中的能力，为生成用于研究BBB功能的人类NVU模型提供了一种逆向工程方法。为了重现这种情况，此类NVU模型还必须整合ECM，以为NVU的细胞提供具有适当机械和生化线索的三维环境。在本综述中，我们首先概述了NVU的细胞和周围的ECM，然后讨论了在整合到NVU模型中时用于模拟ECM的水凝胶所需的特性（硬度、功能和孔隙率）。我们总结了可用于测量BBB功能的方法，并介绍了用于开发强大且可转化的NVU模型的技术，包括Transwell模型、水凝胶模型、3D生物打印、微流控模型和类器官。将无疾病特异性基因突变或有疾病特异性基因突变的iPSC整合到这些NVU模型中，提供了一个研究正常和疾病机制、测试BBB对药物的通透性、筛选新的治疗靶点和药物或设计基于细胞的疗法的平台。
