EAGER: Biomanufacturing the hematopoietic stem cell niche

EAGER：造血干细胞生态位的生物制造

• 批准号: 1547811
• 负责人: Brendan Harley
• 金额: $ 29.96万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1547811&HistoricalAwards=false
• 关键词: EAGER; Biomanufacturing; hematopoietic; stem; cell

PI: Harley, Brendan Proposal Number: 1547811Hematopoiesis is the process where all the body's blood and immune cells are generated from a small number of hematopoietic stem cells (HSCs). These events take place in, and are controlled by, unique regions of the bone marrow termed 'niches.' The investigators are developing an artificial bone marrow that provides the correct sequence of niche signals to expand HSCs for clinical use to treat diseases such as leukemia. However, the rising complexity of these artificial marrow biomaterials requires new tools to help optimize their design. The investigators will demonstrate an approach that combines these experimental studies with computational tools capable of modeling complex systems. This integrated approach will provide important new knowledge regarding how stem cell biomanufacturing systems can be designed to control all phases of HSC activity.The objective of this project is to demonstrate a new paradigm for advanced stem cell manufacturing. Hematopoiesis is the process where the body's blood and immune cells are generated from a small number of hematopoietic stem cells (HSCs) whose behavior is regulated by regions of the bone marrow termed niches. There is an unmet clinical need for stem cell biomanufacturing approaches to selectively expanding donor HSCs while also priming them for HSC transplants used to treat a wide range of hematologic diseases. The investigators have developed a microfluidic platform (engineered marrow analog - eMA) to generate, then sustain in culture, libraries of optically-translucent hydrogels containing overlapping patterns of marrow-inspired niche signals. Using a series of variants of increasing complexity the investigators will dissect how combinations of microenvironmental cues impact HSC fate decisions. However, the complexity of these studies demand a theoretical framework to provide insight regarding how the complex system of signals within the eMA influence HSC behavior. Thus the investigators will combine experimental studies with a rules-based modeling framework to describe how constellations of engineered niche signals dynamically influence HSC fate. This project has two aims: Aim 1: Construct and validate an experimental-modeling framework to monitor the dynamics of HSC fate specification in response to eMA culture. Aim 2: Demonstrate predictive power for scaling eMAs that promote HSC self-renewal. The boarder impacts of this effort are to train and empower the next generation of engineers to address emergent challenges at the intersection of biological, physical, and quantitative sciences. Additionally, the integrated experimental and theoretical approach to efficiently control stem cell fate demonstrated here will be of significant interest to the stem cell biomanufacturing community.

PI：哈雷，布兰登 提案编号：1547811造血是一个过程，其中所有的身体的血液和免疫细胞是从少量的造血干细胞（HSC）产生。这些事件发生在骨髓中被称为“壁龛”的独特区域，并受其控制。研究人员正在开发一种人工骨髓，它提供正确的小生境信号序列，以扩增HSC，用于临床治疗白血病等疾病。然而，这些人工骨髓生物材料日益复杂，需要新的工具来帮助优化其设计。研究人员将展示一种将这些实验研究与能够模拟复杂系统的计算工具相结合的方法。这种综合的方法将提供重要的新知识，关于如何干细胞生物制造系统可以被设计成控制HSC activity.Objective的各个阶段，这个项目是为了展示先进的干细胞制造的新范例。造血是身体的血液和免疫细胞从少量造血干细胞（HSC）产生的过程，造血干细胞的行为由称为小生境的骨髓区域调节。临床上对干细胞生物制造方法的需求尚未得到满足，该方法可以选择性扩增供体HSC，同时也为用于治疗多种血液病的HSC移植做好准备。研究人员开发了一种微流体平台（工程骨髓类似物-eMA），以产生，然后在培养中维持，光学半透明水凝胶库包含骨髓启发的利基信号的重叠模式。使用一系列日益复杂的变体，研究人员将剖析微环境线索的组合如何影响HSC的命运决定。然而，这些研究的复杂性需要一个理论框架来提供关于eMA内复杂的信号系统如何影响HSC行为的见解。因此，研究人员将联合收割机实验研究与基于规则的建模框架相结合，以描述工程小生境信号的星座如何动态影响HSC的命运。该项目有两个目标：目标1：构建并验证一个实验建模框架，以监测eMA培养对HSC命运规范的动态影响。目的2：证明对促进HSC自我更新的扩展eMA的预测能力。这一努力的更广泛的影响是培养和授权下一代工程师，以应对生物，物理和定量科学交叉领域的紧急挑战。此外，综合实验和理论的方法，以有效地控制干细胞的命运，在这里证明将显着的兴趣，干细胞生物制造界。