This proposal will investigate the mechanisms directing hematopoietic stem cell (HSC) fate decisions. AsHSC must meet the demands for a life-long supply of all the mature blood cells, fate decisions have to betightly regulated. As HSC differentiate to increasingly mature cells, self-renewal capability is progressivelylost. Of particular interest is how HSC interactions with the bone marrow microenvironment affect thebalance of self-renewal and differentiation. Our cDNA array analysis of the three most immature murinehematopoietic subpopulations revealed that many components of cell communication complexes aredifferentially regulated. Here, the functional role of particularly interesting molecules will be tested.
In Aim 1 we will assess the use of the adhesion protein ESAM1 as a specific HSC cell surface marker, and determinethe function of ESAM1 in HSC biology using existing ESAM1 knockout mice.
Aim 2 will test whether newlydiscovered receptor-ligand pairs play a role in HSC migration as they do in non-hematopoietic systems.Together, these aims will provide novel insights into the regulation of HSC location, migration and cell fatedecisions by both microenvironmental and HSC intrinsic mechanisms. These studies are relevant to bonemarrow transplantation, autoimmune disease and leukemia.
|Ooi, A G Lisa; Karsunky, Holger; Majeti, Ravindra et al. (2009) The adhesion molecule esam1 is a novel hematopoietic stem cell marker. Stem Cells 27:653-61|
|Attema, Joanne L; Papathanasiou, Peter; Forsberg, E Camilla et al. (2007) Epigenetic characterization of hematopoietic stem cell differentiation using miniChIP and bisulfite sequencing analysis. Proc Natl Acad Sci U S A 104:12371-6|
|Forsberg, E Camilla; Serwold, Thomas; Kogan, Scott et al. (2006) New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 126:415-26|