The goal of this proposal is to understand how innate immune signaling contributes to the formation of hematopoietic stem cells (HSCs) in the embryo. Understanding how HSCs form, and in particular the signaling pathways that are involved in embryonic HSC formation will be essential for producing and expanding HSCs from other cell sources ex vivo, which is a major goal in regenerative medicine. All adult HSCs are derived from hemogenic endothelial cells in the embryo. Hemogenic endothelium is located in several anatomic sites including the yolk sac and the major arteries, but only hemogenic endothelium in the major arteries produces HSCs. We and others discovered that multiple innate immune and inflammatory signaling pathways regulate HSC formation in the major arteries of mouse and zebrafish embryos. This proposal focuses on the contribution of toll-like receptor (TLR) signaling to embryonic HSC formation. We will determine which arms of toll-like receptor signaling pathways, and which toll-like receptors regulate HSC formation, and at which steps in the process they act. We will also examine whether toll-like receptor signaling during HSC formation in the embryo introduces long-term alterations to the function, transcriptome, and epigenome of adult HSCs.
Hematopoietic stem cells are the source of all blood cells throughout our lifetime. The first hematopoietic stem cells form in utero. The goal of this research is to identify some of the important molecules that regulate the formation of hematopoietic stem cells in the embryo. The research may ultimately provide new reagents for generating hematopoietic stem cells from other cell sources for use in transplantation.
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