Hepatic stellate cell progenitor cells

Abstract

Hepatic stellate cells (HSCs) are recognized as a major player in liver fibrogenesis. Upon liver injury, HSCs differentiate into myofibroblasts and participate in progression of fibrosis and cirrhosis. Additional cell types such as resident liver fibroblasts/myofibroblasts or bone marrow cells are also known to generate myofibroblasts. One of the major obstacles to understanding the mechanism of liver fibrogenesis is the lack of knowledge regarding the developmental origin of HSCs and other liver mesenchymal cells. Recent cell lineage analyses demonstrate that HSCs are derived from mesoderm during liver development. MesP1-expressing mesoderm gives rise to the septum transversum mesenchyme before liver formation and then to the liver mesothelium and mesenchymal cells, including HSCs and perivascular mesenchymal cells around the veins during liver development. During the growth of embryonic liver, the mesothelium, consisting of mesothelial cells and submesothelial cells, migrates inward from the liver surface and gives rise to HSCs and perivascular mesenchymal cells, including portal fibroblasts, smooth muscle cells around the portal vein, and fibroblasts around the central vein. Cell lineage analyses indicate that mesothelial cells are HSC progenitor cells capable of differentiating into HSCs and other liver mesenchymal cells during liver development.

Figure 1

Classification of liver mesenchymal cell types in mouse developing livers. HSCs associated with hepatoblasts express desmin and p75NTR. PMCs around the vein express the HSC markers, Jagged1, and SMA. Mesothelial cells covering liver surface express ALCAM, Podoplanin, and WT1. Submesothelial cells associated with mesothelial cells show an intermediate phenotype between mesothelial cells and HSCs. The mesothelium consisting of mesothelial cells and submesothelial cells gives rise to HSCs and PMCs during mouse liver development (arrows).

Figure 2

Summary of cell lineage analyses of HSCs during mouse liver development. MesP1⁺ mesoderm in early embryos gives rise to Wilms tumor 1 (WT1)⁺ septum transversum mesenchyme (STM). At the onset of liver development, the STM adjacent to the foregut endoderm gives rise to the WT1⁺ mesothelium and WT1⁻ liver mesenchymal cells including HSCs and PMCs. In later stages, the mesothelium migrates inward from the liver surface and gives rise to HSCs and PMCs including portal fibroblasts and smooth muscle cells around the portal vein and fibroblasts around the central vein. The WT1⁺ mesothelium does not contribute to hepatoblasts, endothelial cells, or Kupffer cells in liver development.