EAGER: Biomanufacturing the hematopoietic stem cell niche

University Of Illinois At Urbana-Champaign, Urbana IL

Investigators

Abstract

PI: Harley, Brendan Proposal Number: 1547811 Hematopoiesis 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.