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.

Indiana University-Purdue University Indianapolis (IUPUI) / The maternal liver shows marked growth during pregnancy to accommodate the development and metabolic needs of the placenta and fetus. Previous study has shown that the maternal liver grows proportionally to the increase in body weight during gestation by hyperplasia and hypertrophy of hepatocytes. As the maternal liver is enlarged, the transcript level of Ascl1, a transcription factor essential to progenitor cells of the central nervous system and peripheral nervous system, is highly upregulated. The aims of the study were to (1) identify hepatic Ascl1-expressing cells, and (2) study the functions of Ascl1 in maternal liver during pregnancy. In situ hybridization shows that most cell types (parenchymal, nonparenchymal, and mesothelial cells) express Ascl1 mRNA in maternal livers during gestation and in male regenerating livers. Notably, hepatic mesothelial cells abundantly express Ascl1 during pregnancy and liver regeneration. Inducible ablation of Ascl1 gene during pregnancy results in maternal liver enlargement, litter size reduction, and fetal growth retardation. In addition, maternal hepatocytes deficient in Ascl1 gene lack majority of their cytosols and exhibit β-catenin nuclear translocation, while maintaining their cellular boundary and identity. In summary, in both maternal liver during pregnancy and regenerating liver, the expression of Ascl1 is induced in most cell types. Mesothelial cells are potential origin of Ascl1-expressing cells. Ascl1 gene is essential for the progression of normal pregnancy