The role of stem cells in physiology, pathophysiology, and therapy of the liver

Abstract

The objectives of the present review is to update readers with the rapidly changing concepts in liver stem cell biology and related clinical applications. The liver has adapted to the inflow of ingested toxins by the evolutionary development of unique regenerative properties and responds to injury or tissue loss by rapid division of the mature cells, hepatocytes, and bile duct epithelial cells. Proliferation of the parenchymal cells is regulated by numerous cytokine/growth factor-mediated pathways and is timely synchronized with extracellular matrix degradation and the restoration of the vasculature. The putative role of stem cells in physiology, pathophysiology, and therapy is not yet precisely known but currently is under intensive investigation. Resident hepatic stem/ progenitor cells have been identified in small numbers and implicated in liver tissue repair, when hepatocyte and bile duct replication capacity is exhausted or experimentally inhibited. Several independent reports have suggested that bone marrow cells can give rise to different hepatic epithelial cells types, including hepatic stem cells, hepatocytes, and bile duct epithelium. These observations have resulted in the hypothesis that extrahepatic stem cells, specifically bone marrow-derived stem cells, are an important source for liver epithelial cell replacement, particularly during chronic injury. Most of published data, however, now suggest that they do not play a relevant role in replacement of epithelial cells in any known form of hepatic injury. In vitro differentiation protocols for various adult extrahepatic stem cells might eventually provide valuable sources of cells for transplantation and therapy. Amniotic epithelial stem cells, fetal liver progenitor cells as well as embryonic stem cells currently emerge as alternative stem cell sources and open new possibilities for cellular therapies of liver disease.

Murine Embryonic Stem Cell-Derived Hepatic Progenitor Cells Engraft in Recipient Livers with Limited Capacity of Liver Tissue Formation

“…Hamazaki and coworkers were among the first to generate a high percentage of hepato-hepatic phenotype in the last years (1,8,22,25,29,31,33,34,37). However, most of the currently available data cyte precursors from murine ES cell cultures in the presence of growth factors (10).…”

Tumor-initiating stem cells in liver cancer

“…15,16 Consequently, despite their quiescent state, hepatocytes may be considered functional liver stem cells, with very high clonogenic potential, as demonstrated by serial transplantation experiments. 17 In parallel to what we know from these rodent models, inhibition of replication of mature hepatocytes also exist in human liver diseases. Recently, it has been shown that hepatocytes are senescent owing to telomere shortening, in the cirrhotic stage of a wide variety of chronic human liver diseases.…”

Engineered MSCs from Patient-Specific iPS Cells

“…In addition to stem cell mobilizing strategies [56] and bioartificial liver devices (BAL) [78], several alternative cell-based therapies have been investigated to recover unstable conditions in chronic liver disorders as well as during metabolic or acute liver failure. In general the disorders are treated by transplantation of bone marrow hematopoietic, mesenchymal, and mononuclear cell populations (for review see [93] and [74]). The first evidence indicating MSC infusion in mice models could recover liver failure was suggested by Petersen et al showing the presence of bone marrow-derived hepatic cells from sex-mismatched donors in the recipient mice livers [65].…”