Genetic Reg. of Hematopoietic Stem Cell Mobilization

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Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into peripheral blood is a biological phenomenon that is not understood at the molecular level and little is known about the physiologic importance of it. It is notable that there is significant inter-individual variability in humans and inter-strain variability in mice in the ability to mobilize hematopoietic stem and progenitor cells (HSPCs) suggesting that there is genetic regulation of mobilization. In the murine system, a locus on chromosome 11 has been linked to an inter-strain variation in granulocyte colony- stimulating factor (G-CSF) induced stem cell mobilization proficiency. The gene or genes regulating this variation may play an important role in localization and in trafficking of HSPCs. As there is a growing clinical need for hematopoietic stem cell based therapies, it will be important to understand the physiological regulation of stem cell localization, mobilization, and trafficking. This proposal aims at the identification of the gene on chromosome 11 that is a physiologic regulator of HSPC mobilization by generating sub-congenic animals and subsequent functional analysis of individual genes in the genomic interval linked to mobilization by RNA interference. We will also analyze the function of the locus/gene in trans-endothelial migration and adhesion of HSPCs. Finally, using congenic animals in competitive transplantation/mobilization assays, we will analyze the correlation between mobilization proficiency and trafficking of HSPCs to either non-hematopoietic niches, e.g. to muscle tissue, or to other hematopoietic niches.