Excellence in Research: Human Stem Cell-Derived Polarized Dorsoventral Forebrain Organoid: Effect of Matrix Stiffness and Mechanical Stimulus

卓越研究：人类干细胞衍生的极化背腹前脑类器官：基质硬度和机械刺激的影响

• 批准号: 2100987
• 负责人: Yeoheung Yun
• 金额: $ 48.98万
• 依托单位: North Carolina Agricultural & Technical State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2100987&HistoricalAwards=false
• 关键词: Excellence; Research; Human; Stem; Cell

This award will support research that advances our understanding of the biophysical cues that determine stem cell fate. All tissues and organs are derived from stem cells, and a complex array of signals influence the development of stem cells into specific tissue types. The “fate” of a stem cell, which means the specific cell type it ultimately becomes, depends on cues to the cells during organ development. These cues can be biochemical, biophysical or a combination. This work will focus on the development of the brain and the biophysical signals that influence this process. This work will use “organoids” – small three-dimensional cellular structures grown in a lab to mimic the physiology and function of the full-sized organ. Many studies have used brain organoids to examine the biochemical cues that influence the development of stem cells into brain tissue. However, relatively few have studied the biophysical regulation of stem cell differentiation under both static (constant) and dynamic (varying) stimuli. This work will first develop a micro-device to generate consistent and controllable static and dynamic forces. This device will be used to characterize the mechanobiology of organ development. Understanding the mechanical cues that determine the brain organoid’s stem cell fate can ultimately provide new opportunities for studying neurological or neurodegenerative disorders, personalized treatment, cancer, and the effects and treatments of traumatic brain injury. This research involves several disciplines, including micro-device development, mechanobiology, stem cell engineering, materials science, and computational medicine. This project will ultimately advance our knowledge of brain tissue engineering, regenerative medicine, biomanufacturing, and pharmacology, and will be of significant interest to the next-frontier workforce, leading to the clinical and industrial success of such engineering systemsUnderstanding the roles of the biological cues that regulate lineage-specific differentiation of stem cells is critical to the development of polarized organoid structures. However, much of the current literature has focused on the role of biochemical stimuli to generate region-specific brain organoids, rather than on biophysical stimuli, the focus of this work. This work will address this imbalance by discovering how morphogenetic chemicals, extracellular matrix (ECM) stiffness, and mechanical stimuli affect the development of dorsoventral polarized and cortical forebrain organoids in a spatiotemporal manner. This work will provide new knowledge addressing the roles of soluble morphogenetic factors and gradients, ECM mechanics, mechanical stimuli, and signaling pathways in seamlessly regulating organoid differentiation and organization.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项将支持研究，促进我们对决定干细胞命运的生物物理线索的理解。 所有的组织和器官都来源于干细胞，一系列复杂的信号影响干细胞发育成特定的组织类型。干细胞的“命运”，也就是它最终变成的特定细胞类型，取决于器官发育过程中细胞的线索。 这些线索可以是生物化学的，生物物理的或组合。这项工作将侧重于大脑的发展和影响这一过程的生物物理信号。这项工作将使用“类器官”-在实验室中生长的小型三维细胞结构，以模拟全尺寸器官的生理和功能。许多研究使用脑类器官来检查影响干细胞发育成脑组织的生化线索。然而，相对较少的研究干细胞分化的生物物理调节下的静态（恒定）和动态（变化）的刺激。这项工作将首先开发一个微型设备，以产生一致的和可控的静态和动态的力量。 该器械将用于表征器官发育的机械生物学。了解决定脑类器官干细胞命运的机械线索最终可以为研究神经系统或神经退行性疾病，个性化治疗，癌症以及创伤性脑损伤的影响和治疗提供新的机会。这项研究涉及多个学科，包括微器件开发，机械生物学，干细胞工程，材料科学和计算医学。该项目将最终推进我们的脑组织工程，再生医学，生物制造和药理学的知识，并将是下一个前沿的劳动力的重大利益，导致临床和工业成功的工程systemsUnderstanding的生物线索，调节干细胞的谱系特异性分化的作用是至关重要的极化类器官结构的发展。然而，目前的大部分文献都集中在生物化学刺激产生区域特异性脑类器官的作用上，而不是生物物理刺激，这是这项工作的重点。这项工作将通过发现形态发生化学物质，细胞外基质（ECM）硬度和机械刺激如何以时空方式影响背腹极化和皮质前脑类器官的发育来解决这种不平衡。这项工作将提供新的知识解决可溶性形态发生因子和梯度，ECM力学，机械刺激和信号通路在无缝调节类器官分化和organization.This奖项反映了NSF的法定使命的作用，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

项目成果

TERMIS AM

术语上午

• 发表时间: 2023
• 期刊: Development of Cortical Spheroid Tissue Constructs with Perfusable Microvasculature Platform
• 作者: Teal Russell, Qassim Dirar

SOUTHERN BIOMEDICAL ENGINEERING CONFERENCE

南方生物医学工程大会

• 发表时间: 2022
• 期刊: Vascularized Cortical Organoid Microphysiological System To Model Alzheimer’s Disease
• 作者: Yeoheung Yun