Cellular and Molecular Characterization of the Hematopoietic Niche
Hematopoiesis occurs in specialized hematopoietic niches in the adult bone marrow, which provide key regulatory factors and interactions that regulate self-renewal and differentiation of hematopoietic stem cells (HSC). Perturbation within these specialized microenvironments may impose aberrant function on HSC and/or other targets to result in a variety of hematological diseases and dysfunctions including leukemia. There are increasing evidences suggest leukemia cells can take over normal hematopoietic niches to support their self-renewal and to escape from chemotherapy. The overall goal of our laboratory is to develop a complete cellular and molecular understanding of bone marrow microenvironment and their role on leukemia initiation and progression. Better understanding of bone marrow microenvironment will allow us to devise specific strategies to improve current therapeutic solutions and provide better treatment and prevention for leukemia.
We have pioneered an in vivo ectopic bone-forming assay to dissect the developing HSC niche and identified a novel osteochondral progenitor as the HSC niche-initiating cell (Nature 457:490-494, 2009). These findings have allowed for the very first time the development of an in vivo hematopoietic niche model to dissect the cellular/molecular components of niche and the role of niche on leukemia initiation and progression. Reconstruction and more complete definition of the hematopoietic niche is necessary to maximize as well as manipulate HSC potential in both normal and disease states. Abilities to manipulate the niche will have great therapeutic potential. We will use the combination of in vivo ectopic bone-forming assay, single cell gene assay and flow cytometry to address fundamental and outstanding questions related to the HSC niche.