Engineering platforms to recapitulate HSC development ex vivo
We study the vascular microenvironment of the aorta-gonad-mesonephros region (AGM), where HSCs first arise from endothelial precursors in the early embryo, and the fetal liver, where HSCs further mature and expand prenatally. We model these microenvironments with endothelial stroma that provides unique signals sufficient to support HSC generation and self-renewal in vitro.
Single cell approaches to study the dynamics of HSC development
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 and self-renewal, 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).
Molecular analysis of niche cells supporting HSC development
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.
Modeling developmental hematopoiesis in vitro using pluripotent stem cells
We apply knowledge gained from studies of HSC development in embryo models, such as the roles of vascular niche signals and biomechanical forces, and how these signals are integrated, to recapitulate developmental hematopoiesis and generate 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).
Elucidating the prenatal origins of pediatric leukemias
Building on our work in normal developmental hematopoiesis, we are collaborating with Drs. Soheil Meshinchi, Irv Bernstein, Tina Termini, Scott Furlan, and Jay Sarthy 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 and in vivo leukemia models to determine the contribution of the vascular niche in promoting leukemia initiation and resistance to chemotherapy.
Development of HSC-independent immune cells during embryonic hematopoiesis
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.