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 unique parts of the bone marrow termed 'niches'. The genetic information required to direct HSC behaviors such as long-term inactivity, self-renewal, or differentiation to produce blood and immune cells is contained within its DNA, but external signals from the niche are required to trigger these events. And while HSCs are responsible for producing nearly one trillion hematopoietic cells per day such as platelets and immune cells, mutations in this process are responsible for hematopoietic pathologies such as leukemia. However, it is difficult to study these events inside the bone marrow. The long-term goal of this project is to build an artificial bone marrow that provides the correct sequence of niche signals to grow HSCs in the laboratory. Such a tool would be transformative because it would allow one both untangle the web of cues that define HSC niches as well as engineer variants to assist a range of hematopoietic and cancer biology studies. To that end, the group has created a bone marrow biochip platform that reduces the complexity of HSC niches to a manageable series of discrete signals that we can selectively define within a threedimensional biomaterial. This biochip allows to isolate small numbers of HSCs from the bone marrow, manipulate the niche signals surrounding these cells in defined increments, and track their response. This project we will chart how combinations of three important classes of niche signals -- the structural make-up of the bone marrow, supportive niche cells, and biomolecule cues -- impact two critical behaviors, self-renew versus the initiation of differentiation. Such knowledge will be critical for defining how niche signals can be engineered into a biomaterial to control all phases of HSC activity. Through a coordinated research and educational plan, this project will directly support a number of critical outreach programs. Outreach efforts targeting early elementary, secondary, and undergraduate students will be used to broaden participation in science and engineering. Tools developed during this project will serve as the foundation for ongoing and future research projects at the confluence of immunology-biology-engineering disciplines.
