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.

Activated Hepatic Stellate Cells Are Dependent on Self-collagen, Cleaved by Membrane Type 1 Matrix Metalloproteinase for Their Growth

“…Both the cell purity and viability exceeded 95%. Cells cultured for 1-2 days were used as quiescent HSCs (qHSCs), which do not proliferate, contain vitamin A in lipid droplets, and express GFAP but not collagen (3,13). HSCs subcultured for 4 -5 days transdifferentiate spontaneously into activated myofibroblast-like cells, used as aHSCs, which proliferate to induce fibrosis and express ␣SMA, gp46, and collagen.…”

“…They are characterized by the specific feature of taking up vitamin A and depositing it as intracytoplasmic droplets. Recent studies revealed an additional important characteristic of stellate cells in the liver: a pivotal role in liver regeneration (2,3). Despite the diffuse distribution of stellate cells, most detailed investigations of their character have been carried out with cells of hepatic origin.…”

Progenitor Cells in Liver Development, Regeneration and Repair

“…Mesenchymal cells are known to have a critical role in liver regeneration. Stellate cells, fibroblasts, endothelial and kupffer cells are the main types of mesenchymal cells in the liver as well as the sources of growth factors during liver regeneration [3][4][5]. Following acute injury, hepatocytes release mitogenic signals to mesenchymal cells and induce their activation and proliferation.…”

“…Upon transient amplification, these HPCs infiltrate along the liver plate toward the central vein and differentiate into hepatocytes to restore liver function and cell mass [47,48]. Despite all of these studies, the origin of progenitor cells and their migration during liver regeneration remains unclear [3][4][5]. Fibroblast progenitor cells are known to contribute to liver regeneration via activation of Hedghog signaling [49].…”

“…In addition, cholangiocytes play an important role in the local immune response by interacting with immune cells via secreted cytokines that in turn modulates the physiological functions of cholangiocytes as well as surrounding liver cells and invading inflammatory cells [1,2]. Hepatic stellate cells play a major role in liver regeneration following injury via secretion of growth factors such as Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor (HGF), WNT (Wingless/Integrated), VEGF (Vascular Endothelial Growth Factor) and Insulin-like Growth Factor (IGF) [3,4]. Kupffer cells, the resident macrophages within the liver, clear aged red blood cells and pathogens present in the blood through phagocytosis.…”