Liver development, regeneration, and carcinogenesis

Abstract

The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.

Figure 1

The lineage of the developing liver in vivo. Pluripotent embryonic stem (ES) cells from the blastocyst inner cell mass give rise to three principal germ layers: ectoderm, mesoderm, and endoderm. The anterior region of the endoderm will form the foregut. Following hepatic specification of foregut endoderm, hepatic cells (now called hepatoblasts) will bud into the septum transversum and continue to proliferate and differentiate. Maturation into hepatocytes and bile epithelial cells continue until several weeks after birth. The red bars highlight the key stages of liver development. The black bars in the middle are mouse embryos at different stages of development, and the blue bars at the bottom indicate the equivalent stages in human development.