We study the vascular microenvironment of the aorta-gonad-mesonephros region (AGM), where HSCs first arise in the embryo. We model this niche with AGM-derived endothelial stroma, which provides unique signals sufficient to support HSC generation and self-renewal in vitro.
We are using integrated single cell immunophenotypic and functional assays for HSC precursors with single cell RNA-sequencing to identify the dynamic transcriptional programs regulating HSC development, incorporating innovative technologies in single cell omics platforms and computational algorithms developed by our collaborators in the laboratory of Dr. Cole Trapnell (UW Genome Sciences).
We use Integrated scRNAseq analysis to identify intercellular signaling interactions between niche endothelial stroma and HSC precursors guiding development of hemogenic endothelium into functional HSC. Insights from these studies are used to engineer HSC generation in stroma-free systems incorporating Notch pathway receptor agonists and other cooperating niche signals.
We apply knowledge gained from studies of HSC development in the embryo model, such as the role of endothelial cell niche signals and biomechanical forces, to promote generation of multilineage engrafting hematopoietic cells from mouse and human pluripotent stem cells in vitro. This work involves collaborations with the laboratories of Dr. Sergei Doulatov (UW Hematology) and Dr. Ying Zheng (UW Bioengineering).
Building on our work in normal developmental hematopoiesis, we are collaborating with Drs. Quy Le, Soheil Meshinchi, and Irv Bernstein at the Fred Hutch to study the ontogeny of pediatric leukemias and understand how the pathways that regulate HSC development are co-opted by leukemic cells. This collaboration leverages in vitro leukemia models developed by Dr. Le to determine the contribution of the vasculcar niche in promoting leukemia initiation and resistance to chemotherapy.
We study the origin of specialized lineages of immune cells, such as B-1a lymphocytes, that arise uniquely during embryonic development and can contribute to immunity in the adult independently of HSC. This knowledge may contribute to improving immune reconstitution following hematopoietic stem cell transplantation and to engineering novel cellular immunotherapies.