EAGER: Biomanufacturing the hematopoietic stem cell niche

PI：Harley，Brendan提案编号：1547811造血是指体内所有的血液和免疫细胞都是从少量的造血干细胞(HSCs)产生的过程。这些活动发生在骨髓中被称为“小生境”的独特区域，并受其控制。研究人员正在开发一种人造骨髓，它可以提供正确的利基信号序列，以扩大造血干细胞，用于临床治疗白血病等疾病。然而，这些人造骨髓生物材料日益复杂，需要新的工具来帮助优化它们的设计。研究人员将展示一种将这些实验研究与能够对复杂系统建模的计算工具相结合的方法。这一集成的方法将为如何设计干细胞生物制造系统来控制HSC活动的所有阶段提供重要的新知识。该项目的目标是展示先进干细胞制造的新范式。造血是人体的血液和免疫细胞由少量的造血干细胞(HSCs)产生的过程，这些干细胞的行为受到骨髓中被称为壁龛的区域的调节。干细胞生物制造方法在选择性扩增供体造血干细胞的同时，也为用于治疗多种血液病的造血干细胞移植做好了准备，这方面的临床需求尚未得到满足。研究人员开发了一种微流控平台(工程骨髓类似物-EMA)，以产生并在培养中维持包含重叠模式的骨髓激发的利基信号的光学半透明水凝胶库。使用一系列日益复杂的变种，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洞察EMA中复杂的信号系统如何影响HSC行为。因此，研究人员将把实验研究与基于规则的建模框架相结合，以描述工程利基信号的星座如何动态影响HSC的命运。本项目有两个目标：目标1：构建和验证一个实验建模框架，以监控HSC命运规范对EMA文化的动态响应。目标2：展示扩展EMA的预测能力，以促进HSC自我更新。这一努力的更大影响是培训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，这里展示的有效控制干细胞命运的综合实验和理论方法将对干细胞生物制造社区产生重大兴趣。

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.