(A) Hepatic stellate cell development. Lineage-tracing analyses in mice indicate that during development, the mesodermal cells within the septum transversum invade the liver while differentiating into hepatic stellate cells and perivascular mesenchymal cells. VEGF and retinoic acid signaling are both required for hepatic stellate cell formation, potentially affecting the migration of septum transversum cells, the differentiation of hepatic stellate cells, or both. Wt1, Wnt/β-catenin signaling, and Lhx2 inhibit aberrant activation of hepatic stellate cells in the developing liver. (B) Contribution of hepatic stellate cells to hepatic organogenesis. The biological processes influenced by hepatic stellate cells are indicated in blue. For endothelial cells, hepatic stellate cells secrete the chemokine SDF1, whereas endothelial cells express its receptor CXCR4. Concurrently, endothelial cells produce PDGFβ, whereas hepatic stellate cells express its receptor. SDF1α and PDGFβ signaling maintain the close association between hepatic stellate cells and endothelial cells, which is critical for vascular tube formation and integrity. For hematopoietic stem cells (HSCs), hepatic stellate cells mediate their recruitment to the liver via SDF1α/CXCR4 signaling. For hepatic epithelial cells, hepatic stellate cells regulate the proliferation of hepatoblast progenitor cells and hepatocytes by producing growth factors such as Wnt, FGF, HGF, and retinoic acid. They may also modulate the differentiation of hepatocytes and biliary cells from hepatoblasts by controlling the ECM composition within the liver. Lastly, hepatic stellate cells may contribute to the development of biliary cells by expressing the Notch ligand jagged 1 (Jag1).