Extrinsic regulation of Hematopoietic Stem Cells in the fetal liver

Hematopoietic stem cells (HSCs) lie at the top of the hematopoietic hierarchy and give rise to all mature blood cells. They are tightly regulated not only by cell-intrinsic but also cell-extrinsic mechanisms that allow HSCs to respond to dynamic physiological demands of the body. HSCs build the hematopoietic system during development and maintain homeostasis in adults by changing their properties according to different needs. A niche is the microenvironment where HSCs reside and receive extrinsic regulation. Understanding the niche is crucial for elucidating how HSCs are regulated by extrinsic cues. During mammalian development, HSCs pass through several different niches, among which the liver is the major site for their rapid expansion and maturation. The fundamental question of what cells constitute the fetal liver niche in vivo remains largely elusive. It is also unclear whether and how cell-extrinsic maintenance mechanisms accompany changes in HSC properties during ontogeny. Here, I genetically dissected the cellular components of the HSC niche in the fetal liver by identifying the cellular source of a key cytokine, stem cell factor (SCF). In addition, I found that HSCs switch to depend on thrombopoietin (TPO), another key factor, during ontogeny and uncovered the mechanism by which HSCs gain this dependence.