Hepatic stellate cells in liver development, regeneration, and cancer

Abstract

Hepatic stellate cells are liver-specific mesenchymal cells that play vital roles in liver physiology and fibrogenesis. They are located in the space of Disse and maintain close interactions with sinusoidal endothelial cells and hepatic epithelial cells. It is becoming increasingly clear that hepatic stellate cells have a profound impact on the differentiation, proliferation, and morphogenesis of other hepatic cell types during liver development and regeneration. In this Review, we summarize and evaluate the recent advances in our understanding of the formation and characteristics of hepatic stellate cells, as well as their function in liver development, regeneration, and cancer. We also discuss how improved knowledge of these processes offers new perspectives for the treatment of patients with liver diseases.

Figure 1. Models for studying hepatic stellate cells.

(A) Phase contrast image of mouse hepatic stellate cells cultured for 2 days. These hepatic stellate cells are still quiescent, as evidenced by their vitamin A lipid deposition, a stellate morphology, and presence of dendritic processes. (B) Phase contrast image of mouse hepatic stellate cells cultured for 14 days. By this time, hepatic stellate cells are fully activated and exhibit dramatic changes in their morphology and reduction in lipid deposition. (C) Fluorescence image of hepatic stellate cells in healthy adult mouse liver stained for desmin. (D) Fluorescence image shows α-SMA immunostaining in CCl₄-induced fibrosis in the adult mouse liver. (E) Confocal single-plane image of Tg(hand2:EGFP) expression in zebrafish hepatic stellate cells at 5 days after fertilization. The hepatic stellate cells exhibit a stellate morphology and send out complex protrusions (23). (F) Confocal single-plane image of hepatic stellate cells labeled by Tg(hand2:EGFP) expression in zebrafish larvae treated with 2% ethanol from 4 to 5 days after fertilization. Hepatic stellate cells become activated upon the acute ethanol assault, as evidenced by the loss of complex cellular processes and elongated cell body, suggestive of changes in contractility (24).

Figure 2. Hepatic stellate cell development and contribution to liver organogenesis.

(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).

Figure 3. Hepatic stellate cells in liver regeneration and HCC.

The biological processes that are influenced by hepatic stellate cells are indicated in blue. At early phases of liver regeneration, hepatic stellate cells promote the proliferation of liver progenitor cells and hepatocytes. They also stimulate angiogenesis in the wounded area and assist in the recruitment of hematopoietic stem cells and immune cells to the liver (reviewed in ref. 48). Recent studies suggest that activated hepatic stellate cells may undergo a mesenchymal-to-epithelial transition to transdifferentiate into liver progenitor cells. At late phases, hepatic stellate cells participate in the termination of regeneration, likely via high expression of TGF-β. Hepatic stellate cells have also been proposed to contribute to HCC development, potentially through dysregulation of some aspects of liver regeneration described above. On the other hand, liver fibrosis, which results from ectopic hepatic stellate cell activation, has controversial roles in HCC. Most evidence suggests that fibrosis promotes HCC, but it is possible that in some clinical settings fibrosis and HCC might occur due to the same underlying factor(s) rather than one promoting the other.