The liver provides essential functions required to maintain homeostasis and health of many organisms. During embryonic development, hepatocytes and biliary epithelial cells arise from the endoderm layer, whereas nonparenchymal liver cells emerge from the mesoderm layer. In the healthy adult liver, hepatocytes have a very slow turnover rate but retain the capacity to rapidly repopulate the liver upon loss of liver mass. Liver stem cells are called upon to regenerate the liver parenchyma when the ability of hepatocyte proliferation is compromised. Over the years, a wealth of knowledge has accumulated pertaining to the cellular and molecular events of liver stem cell activation and differentiation in various animal models and human liver diseases. This knowledge is the driving force to study stem cells in vitro and apply them in laboratory and clinical practice.

Today, we are witnessing an explosion of advances in stem cell technologies. The development of induced pluripotent stem cells (iPSCs) and the differentiation of stem cells into various cell lineages in vitro over the last decade have greatly expanded our ability to model, diagnose, treat, and prevent various diseases. In particular, stem cell-derived hepatocytes have been used for modeling hepatotropic virus infection, virus and host interaction, and high throughput drug screening, as well as hepatocyte transplantation in animal models. Liver stem cells are also a promising tool in gene modification of genetic abnormalities such as metabolic liver diseases and regeneration of the liver in cases of acute liver failure, cirrhosis, and hepatocellular carcinoma.

Despite the recent progress, great challenges remain. For example, differentiation of stem cells into hepatic lineage is stalled at the stage of hepatocyte-like cells (HLC) failing to achieve fully mature hepatocytes. Further development of HLC into fully matured hepatocytes is required to reach the full potential of its research and clinical applications. Gene editing can cause off-target genetic alterations, a serious safety concern for clinical practice. Grafting of the liver stem cells or HLCs in animal models has had only measured success. Overcoming these shortcomings will get us ever closer to the reality of utilizing stem cells in the treatment of various liver diseases.

The purpose of this special issue is to publish high quality research papers and review articles addressing recent advances in the applications of stem cell technologies for the study of molecular mechanisms of hepatocyte growth and differentiation, pathogenesis, modeling, and therapy of liver diseases. Original, high quality contributions that are not yet published or that are not under review by other journals or peer-reviewed conferences will be considered.

Potential topics include but are not limited to the following:

• New methods for differentiation of hepatic stem cells (including hepatocytes and nonparenchymal cells)
• Application of stem cells derived hepatocytes for
  • Drug screening
  • Modeling drug metabolism
  • Modeling hepatotropic virus infection and virus/host interaction
  • Gene modification
  • Gene regulation
  • Mechanisms of differentiation
• Stem cells in liver development, regeneration, and carcinogenesis
• Novel animal models utilizing stem cell technology for liver diseases study
• Stem cell-based therapies in liver diseases