Improving the interaction of hematopoietic stem cells with the perivascular niche to promote engraftment

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PROJECT SUMMARY/ABSTRACT Hematopoietic stem and progenitor cell (HSPC) transplantation is a curative treatment for many blood diseases and cancers. However, these procedures still need to be optimized to improve patient outcomes and survival. HSPCs reside in a microenvironment surrounded by niche cells that help regulate their function. Our research proposal seeks to address fundamental questions regarding the cellular interactions between HSPCs and niche cells. During development in the embryo, HSPCs move through different tissues and have changing requirements for contact with the microenvironment. HSPCs first arise in the dorsal aorta, a large vessel in the embryo, and are then released into circulation. Next, HSPCs migrate to the fetal liver where the population of cells expands exponentially via symmetric divisions. Finally, HSPCs migrate again to colonize the bone marrow where they will remain throughout adulthood. As HSPCs are migrating between these different hematopoietic tissues, they are also becoming more mature and are programmed towards their adult quiescent state. We use zebrafish and mice as model systems that are highly conserved with humans and have many genetic tools for functional testing and live imaging of cellular behaviors. In zebrafish, we have found a novel role for vascular endothelial growth factor c (vegfc) in the release of HSPCs from the dorsal aorta. Vegfc also regulates a fate decision in pre-HSPCs that determines if they will become a stem cell or a different type of progenitor cell. At later stages, we found a programming function for integrin alpha 4 (itga4) in the caudal hematopoietic tissue (CHT), the zebrafish equivalent of the fetal liver. We hypothesize that the timing of HSPC contact and transitions between developmental niches is critical for their correct programming. We will address this hypothesis through the following Specific Aims: 1) Define the role of vegfc in HSPC transition and release from the dorsal aorta. 2) Determine how itga4-dependent contact with the CHT niche programs HSPCs as they transition from fetal-like to adult stages. We will perform in vivo genetic knockdown and small molecule treatments, together with live imaging, to understand the dynamic interactions between HSPCs and niche cells. We will then translate these results to an in vitro vascular niche that is used to differentiate cells into transplantable HSPCs that could lead to cell-based therapies for patients.