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

脑血管系统的功能性 3D 组织工程模型，包含干细胞来源的脑微血管内皮细胞、周细胞和星形胶质细胞

• 批准号: 10328888
• 负责人: Peter C Searson
• 金额: $ 33.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328888
• 关键词: 3-Dimensional; Achievement; Address; Adult; Advanced Development; Astrocytes; Benchmarking; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Diseases; Cells; Central Nervous System Diseases; Cerebrovascular system; Chemistry; Complex; Development; Disease; Disease Progression; Drug Delivery Systems; Endothelial Cells; Functional disorder; Gene Delivery; Generations; Goals; Health; Human; Immune; Methods; Modeling; Morphology; Nervous system structure; Neurons; Neurosciences Research; Nutrient; Oxidative Stress; Pericytes; Phenotype; Physiological; Problem Solving; Role; Source; Stress; Structure; System; Time; Tissue Engineering; Toxic effect; Toxin; Translations; Umbilical vein; Vascular System; Vascularization; Work; arteriole; brain endothelial cell; cerebral microvasculature; clinically relevant; human model; induced pluripotent stem cell; microphysiology system; network models; neurogenesis; neuroinflammation; neurotoxicity; new technology; novel therapeutics; pathogen; postcapillary venule; prevent; repaired; response; self organization; specific biomarkers; stem cell biology; stem cell technology; stem cells; three dimensional cell culture; tool; vascular tissue engineering; venule

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.

项目摘要 ! 神经血管系统通过600公里的神经网络为成年人大脑中的1000亿个神经元提供营养。 毛细血管和微血管的网络。作为大脑和血管系统之间的界面， 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来改善微环境 和病原体。与此同时，几乎所有的大脑疾病都与大脑的破坏或 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，并最终导致神经炎症、氧化应激和神经毒性。功能性人 模型有可能解决许多未解决的问题， 神经血管系统在健康和疾病中的作用，以及开发更复杂的人类神经模型 该系统将最终有助于实现整合的多细胞系统。 开发生理学相关的组织工程人类模型有两个主要挑战 神经血管系统：（1）相关细胞的来源，以及（2）构建模型的3D细胞培养方法。干细胞 技术提供了一种解决方案，提供可靠的人类大脑特异性细胞来源， 发展血脑屏障模型的障碍。同样，组织工程学的进步为 可灌注血管网络的自组织。解决这些问题将对 神经科学研究，阐明中枢神经系统疾病的机制， 以及新疗法和技术的翻译。在目标1中，我们将描述表型和屏障 脑微血管在静止条件下和响应于激活/应激的功能。在目标2中， 开发和表征脑特异性毛细血管网络。在目标3中，我们将整合周细胞和星形胶质细胞 我们的模型。这些模型将使广泛的应用，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、药物和基因递送以及毒性。