Cell therapy for the diseased liver: from stem cell biology to novel models for hepatotropic human pathogens

Abstract

It has long been known that hepatocytes possess the potential to replicate through many cell generations because regeneration can be achieved in rodents after serial two-thirds hepatectomy. It has taken considerable time and effort to harness this potential, with liver regeneration models involving hepatocyte transplantation developing over the past 15 years. This review will describe the experiments that have established the models and methodology for liver repopulation, and the use of cells other than adult hepatocytes in liver repopulation, including hepatic cell lines and hematopoietic, cord blood, hepatic and embryonic stem cells. Emphasis will be placed on the characteristics of the models and how they can influence the outcome of the experiments. Finally, an account of the development of murine models that are competent to accept human hepatocytes is provided. In these models, liver deficiencies are induced in immunodeficient mice, where healthy human cells have a selective advantage. These mice with humanized livers provide a powerful new experimental tool for the study of human hepatotropic pathogens.

A Novel Mouse Model for Stable Engraftment of a Human Immune System and Human Hepatocytes

“…Humanized mice bearing chimeric human livers represent an important tool to study human hepatotropic infections [ 8 , 9 ]. Liver toxicity generated by hepatocyte-specific expression of the urokinase plasminogen activator (uPA) transgene creates a ‘niche’ for growth of adoptively transferred hepatocytes [ 10 , 11 ].…”

Advances in hepatic stem/progenitor cell biology

“…Many studies have shown the potential of stem cells or isolated HSPCs to rescue a damaged liver when HSPCs have an advantage over damaged hepatocytes in mouse models such as the uPA/SCID and FAH or FRG mouse models (Brezillon et al, 2008[ 8 ]; Grompe et al, 2013[ 30 ]) (Figure 2 (Fig. 2) ).…”

Potential applications of germline cell-derived pluripotent stem cells in organ regeneration

“…The liver tissue mass can be restored after two-thirds hepatectomy, as shown by Higgins and Anderson in the 1930s in rat models. 36 The human liver also contains a population of stem cells as well as bipotential oval cells that can differentiate into hepatocytes when necessary. 37,38 Unfortunately, in severe liver diseases, the hepatocytes' and the liver stem cells' regenerative capacity may be impaired.…”