Mechanisms of Hematopoietic stem cell Specification and Self-Renewal

During an individual’s lifetime, blood-forming cells in the bone marrow called hematopoietic stem cells (HSCs) supply all the red and white blood cells needed to sustain life. These blood stem cells are unique because they can make an identical copy of themselves (self-renew). Disorders of the blood system can be terminal, but such diseases may be cured when patients are treated with a bone marrow transplant. Unfortunately, bone marrow is in short supply due to limited availability of donors, and it is not yet possible to expand HSCs outside of the human body; HSCs that are removed from their native environment, or niche, rapidly lose their ability to self-renew and thus cannot sustain hematopoiesis in a transplant recipient. Furthermore, attempts to make blood stem cells from embryonic stem cells (ESCs) have also proved unsuccessful to date because these “tailored HSCs” are defective in self-renewal as well. These problems suggest that our understanding of the biology of HSCs is not sufficient to foster their maintenance or generation. To address this issue, we propose to study hematopoietic stem cells in the context of mammalian development; the entire complement of a person’s HSCs is made in a very short time window during the first trimester of pregnancy. By increasing our understanding of how HSCs are made and acquire self-renewal in vivo, we hope to develop better methods of generating HSCs in vitro and learn to provide the missing cues to coax them into becoming fully functional, self-renewing hematopoietic stem cells. Specifically, we plan to investigate how the fate decision that delineates blood cells from their embryonic precursor, called specification, is maintained at the molecular level. Second, we are interested in what cell type human HSCs descend from so as to understand what precursor to look for when attempting to differentiate ESCs into blood stem cells. Finally, we plan to apply molecular analyses to the property of self-renewal by looking at cell populations that cover a spectrum with regards to self-renewal: HSCs, cultured HSCs (not self-renewing), HSC precursors (not self-renewing), and ESCs differentiated to non-self-renewing HSCs. These comparisons will help define the molecular regulation of self-renewal, and place ESC-derived progenitors on the spectrum of self-renewal. Through these studies, we hope to better understand blood stem cells as they are made and maintained during human development with the ultimate goal to provide wider access to stem cell-based therapies.