Research
Engineering platforms to recapitulate HSC development ex vivo
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.
Single cell transcriptomic analysis to identify the distinguishing properties of HSC-competent hemogenic endothelium in the mouse embryo.
Credit: Dignum et al, Cell Reports 2021Single 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, 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).
Single cell transcriptomic analyisis of hematopoietic populations supported by culture with AGM-EC or culture in a stromal cell-free engineered niche.
Credit: Hadland et al. BioRxiv 2021Molecular 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.
Directed differentiation of pluripotent stem cells
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).
Elucidating the prenatal origins of pediatric leukemias
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.
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.
Distinct waves of embryonic hematopoiesis contribute differentially to innate B-1a lymphocytes
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