CAREER:Engineering Brain-region-specific Organoids Derived from Human Stem Cells

职业：工程化源自人类干细胞的大脑区域特异性类器官

• 批准号: 1652992
• 负责人: Yan Li
• 金额: $ 50.13万
• 依托单位: Florida State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1652992&HistoricalAwards=false
• 关键词: CAREER; Engineering; Brain; region; specific

PI: Li, YanProposal No: 1652992 The proposed work seeks to generate mini-brains (also called brain organoids) derived from human stem cells with defined structure and function that would mimic human brains. The brain organoids will provide an experimental platform that will enable discovery of novel interventions and pharmacological treatments for people with neurological disorders, such as Alzheimer's disease, Parkinson's disease, and more recently microcephaly in infants.Unavailability of access to human brain tissues limits the discovery of novel interventions and pharmacological treatments for people with neurological disorders, such as Alzheimer's disease, Parkinson's disease, and more recently microcephaly in infants. To address this critical need, the proposed work seeks to generate mini-brains (also called brain organoids) with defined structure and function that would mimic human brains. To achieve this, this project will utilize stem cell-based tissue engineering approach, leveraging the capability of stem cells to self-assemble into brain-like structure under suitable conditions. The proposed research provides a new approach for the understanding of brain tissue development, and a practical and clinically relevant platform for drug discovery and screening. Specifically, this project will generate and characterize homotypic and heterotypic brain-region-specific organoids derived from human stem cells; investigate the influence of extracellular matrix composition and remodeling on the formation of brain-like organoids; and, pattern brain tissue along rostral and caudal axis by modulating the Wnt signaling pathway. The novelty of the proposed research is that additional cell types are incorporated with induced pluripotent stem cell-derived neural spheroids and the extracellular matrices containing signaling molecules such as in Wnt pathway are provided to mimic spatial regulations that occur in human brain. In addition, the project will establish an interactive learning platform to form a bridge between academia and industry, while simultaneously reducing gender disparity and increasing the participation of minority students in engineering. The project will encourage African American and female students to pursue advanced career by recruiting them to participate in the proposed research and education. A broader goal of the proposed work is to establish a stem cell engineering research and education program that will attract underrepresented students for integrated multidisciplinary research and education. The education and outreach plan will accomplish the educational objectives by: establishing mentoring and research projects to attract female and minority students, enhancing Active Learning through Stem cell/Organoid engineering (ALSO) and digital platforms, and building an academia-industry pipeline to supply next-generation bioengineers.

PI：Li, Yan提案编号：1652992 拟议的工作旨在产生源自人类干细胞的迷你大脑（也称为脑类器官），其具有模仿人类大脑的明确结构和功能。 大脑类器官将提供一个实验平台，使人们能够发现针对患有神经系统疾病（例如阿尔茨海默病、帕金森病以及最近的婴儿小头畸形）的新型干预措施和药物治疗方法。无法进入人类大脑组织限制了这些疾病的发现针对患有神经系统疾病（例如阿尔茨海默病、帕金森病以及最近的婴儿小头畸形）的患者提供新的干预措施和药物治疗。为了满足这一迫切需求，拟议的工作旨在生成具有模仿人类大脑的明确结构和功能的迷你大脑（也称为大脑类器官）。为了实现这一目标，该项目将利用基于干细胞的组织工程方法，利用干细胞在适当条件下自组装成类脑结构的能力。拟议的研究为理解脑组织发育提供了一种新方法，并为药物发现和筛选提供了实用且临床相关的平台。具体来说，该项目将生成并表征源自人类干细胞的同型和异型大脑区域特异性类器官；研究细胞外基质组成和重塑对类脑类器官形成的影响；并且，通过调节 Wnt 信号通路沿头轴和尾轴形成脑组织模式。 该研究的新颖之处在于，将额外的细胞类型与诱导多能干细胞衍生的神经球体相结合，并提供含有Wnt通路等信号分子的细胞外基质，以模拟人脑中发生的空间调节。此外，该项目还将建立一个互动学习平台，在学术界和工业界之间架起一座桥梁，同时减少性别差异，增加少数族裔学生对工程的参与。 该项目将通过招募非裔美国学生和女学生参与拟议的研究和教育来鼓励她们追求高级职业。拟议工作的更广泛目标是建立干细胞工程研究和教育计划，吸引代表性不足的学生进行综合多学科研究和教育。教育和推广计划将通过以下方式实现教育目标：建立指导和研究项目以吸引女性和少数族裔学生，通过干细胞/类器官工程（ALSO）和数字平台加强主动学习，以及建立学术界和工业界的管道以提供下一代-一代生物工程师。

项目成果

Human Stem Cell-derived Aggregates of Forebrain Astroglia Respond to Amyloid Beta Oligomers

• DOI: 10.1089/ten.tea.2019.0227
• 发表时间: 2020-05-01
• 期刊: TISSUE ENGINEERING PART A
• 影响因子: 4.1
• 作者: Griffin, Kyle;Bejoy, Julie;Li, Yan
• 通讯作者: Li, Yan

Genomics Analysis of Metabolic Pathways of Human Stem Cell-Derived Microglia-Like Cells and the Integrated Cortical Spheroids

• DOI: 10.1155/2019/2382534
• 发表时间: 2019-11-18
• 期刊: STEM CELLS INTERNATIONAL
• 影响因子: 4.3
• 作者: Bejoy, Julie;Yuan, Xuegang;Li, Yan
• 通讯作者: Li, Yan

The Use of Pluripotent Stem Cell-Derived Organoids to Study Extracellular Matrix Development during Neural Degeneration

• DOI: 10.3390/cells8030242
• 发表时间: 2019-03
• 期刊: Cells
• 影响因子: 6
• 作者: Yuanwei Yan;Julie Bejoy;Mark Marzano;Yan Li

Differential Effects of Heparin and Hyaluronic Acid on Neural Patterning of Human Induced Pluripotent Stem Cells

• DOI: 10.1021/acsbiomaterials.8b01142
• 发表时间: 2018-12-01
• 期刊: ACS BIOMATERIALS SCIENCE & ENGINEERING
• 影响因子: 5.8
• 作者: Bejoy, Julie;Wang, Zhe;Li, Yan
• 通讯作者: Li, Yan

Cell population balance of cardiovascular spheroids derived from human induced pluripotent stem cells

人诱导多能干细胞来源的心血管球体的细胞群平衡

• DOI: 10.1038/s41598-018-37686-1
• 发表时间: 2019
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Yan, Yuanwei;Bejoy, Julie;Xia, Junfei;Griffin, Kyle;Guan, Jingjiao;Li, Yan
• 通讯作者: Li, Yan