Functional 3D tissue-engineering models of the cerebrovasculature incorporating stem cell-derived brain microvascular endothelial cells, pericytes, and astrocytes

项目摘要 好了！ 神经血管系统通过600公里向成人大脑中的1000亿个神经元提供营养。 毛细血管和微血管网络。作为大脑和血管系统之间的接口， 血脑屏障，包括神经血管系统，负责调节大脑。 通过防止化学波动、免疫细胞的运输和毒素的进入而形成的微环境 和病原体。与此同时，几乎所有的大脑疾病都与干扰或 神经血管功能障碍，导致血液成分、免疫细胞和病原体进入 进入大脑，最终导致神经炎症、氧化应激和神经毒性。功能型人类 模型有可能解决与角色相关的许多未解决的问题 神经血管学在健康和疾病以及开发更复杂的人类神经模型中的作用 这一系统最终将有助于实现综合多蜂窝系统。 开发与生理相关的人类组织工程模型有两个主要挑战 神经血管学：(1)相关细胞来源；(2)三维细胞培养方法建立模型。干细胞 技术提供了一种解决方案来提供可靠的人类大脑特定细胞来源，这是一个长期存在的 发展血脑屏障模型的障碍。同样，组织工程学的进步也为 可灌流的血管网络的自组织。这些问题的解决将对 神经科学研究，阐明中枢神经系统疾病的机制，并在发展中 以及新疗法和新技术的翻译。在目标1中，我们将描述表型和障碍 脑微血管在静止状态下和对激活/应激反应的功能。在《目标2》中我们将 开发和表征特定于大脑的毛细血管网络。在目标3中，我们将整合周细胞和星形胶质细胞 进入我们的模型。这些模型将实现广泛的应用，包括基础研究 神经发生、血管形成和发育，以及疾病进展、治疗、 修复，药物和基因输送，以及毒性。

Project Summary ! The neurovasculature supplies nutrients to the 100 billion neurons in the adult human brain via a 600 km network of capillaries and microvessels. As the interface between the brain and the vascular system, the blood-brain barrier, which includes the neurovasculature, is responsible for regulating the brain microenvironment by preventing fluctuations in chemistry, transport of immune cells, and the entry of toxins and pathogens. At the same time, almost all diseases of the brain are associated with disruption or dysfunction of the neurovasculature, which leads to entry of blood components, immune cells, and pathogens into the brain, and ultimately causes neuroinflammation, oxidative stress, and neurotoxicity. Functional human models have the potential to address many unresolved questions associated with the role of the neurovasculature in health and disease, and in developing more complex models of the human nervous system that will ultimately contribute towards the realization of integrated multicellular systems. There are two major challenges to developing physiologically-relevant, tissue-engineered models of the human neurovasculature: (1) a source of relevant cells, and (2) 3D cell culture methods to build the model. Stem cell technology provides a solution to providing a reliable source of human, brain-specific cells, a long-standing barrier to developing blood-brain barrier models. Similarly, advances in tissue engineering provide the tools for self-organization of perfusable vascular networks. Solving these problems will have significant impact on neuroscience research, elucidating mechanisms of central nervous system diseases, and in the development and translation of new therapies and technologies. In Aim 1 we will characterize the phenotype and barrier function of brain microvessels under quiescent conditions and in response to activation/stress. In Aim 2 we will develop and characterize brain-specific capillary networks. In Aim 3 we will integrate pericytes and astrocytes into our models. These models will enable a broad range of applications, including fundamental studies of neurogenesis, vascularization, and development, and mechanistic studies of disease progression, treatment, repair, drug and gene delivery, and toxicity.