Grant: CIHR Fellowship

Hematopoietic stem and progenitor cells (HSPC) are cells that self-renew and give rise to all the mature blood and immune cells in the body. During fetal development, HSPCs reside in the mammalian liver, a short-term site for blood and stem cell production. The HSPCs then migrate to the bone marrow which becomes the primary site of blood and stem cell production for the rest of life. Under disease conditions where the marrow is unable to produce blood stem cells, HSPCs migrate to non-blood stem cell producing sites, such as the liver and spleen, and undergo inefficient process of blood cell production. It is unclear what makes the liver, which was once the primary site of HSPC function during fetal development, inefficient in blood production during disease. The development and function of the HSPCs in the marrow depends on its microenvironment, the primary component of which is the vascular endothelial cells (ECs). A subtype of the vascular ECs, known as venous sinusoidal endothelial cells (SECs), are important for supporting HSPC maintenance function. The main objective of this research proposal is to characterize the marrow microenvironment at the DNA level and identify regulatory factors that are specifically expressed in SECs of the adult marrow and drive expression of genes that support HSPC function. I will first use different sequencing techniques to characterize the regulatory factors that are specifically expressed in the zebrafish marrow and support HSPC function. The regulatory factors will be overexpressed in zebrafish liver ECs to alter them to gain HSPC supportive function. I will also overexpress the regulatory factors in human induced pluripotent stem cells, which can divide into different cell types, to change them to become ECs with HSPC supportive function. These generated ECs will then be co-cultured with HSPCs to determine if they can stimulate human HSC fate and proliferation and generate an artificial environment for HSPC function in mice.