Liver Stem Cells: Experimental Findings and Implications for Human Liver Disease

Abstract

Evidence from human histopathology and experimental studies with rodents and zebrafish has shown that hepatocytes and cholangiocytes may function as facultative stem cells for each other in conditions of impaired regeneration. The interpretation of the findings derived from these studies has generated considerable discussion and some controversies. This review examines the evidence obtained from the different experimental models and considers implications that these studies may have for human liver disease. Few topics of liver tissue biology have attracted as much attention as the existence of liver-specific tissue stem cells. Routine liver histology reveals two types of epithelial cells, hepatocytes and cholangiocytes (also known as biliary epithelial cells). Endothelial cells line the hepatic capillaries (sinusoids), with macrophages (Kupffer cells) interspersed along the sinusoid lumen. Stellate cells exist under the sinusoids and in close proximity to hepatocytes. None of these cells appears to have functions of a fully committed tissue specific stem cell, analogous to the cells of the intestinal crypts, the basal layer of the epidermis, bone marrow stem cells, etc. Hepatocytes and cholangiocytes can be easily identified based on their morphology and cell-specific biomarkers. Hepatocytes and cholangiocytes, however, often have mutually mixed expression of biomarkers in pathologic conditions. In patients with fulminant hepatic failure (FHF), there is rampant proliferation of cholangiocytes organized in ductular structures (“ductular reaction”1, 2). Many of these cholangiocytes (known as ductular hepatocytes) express biomarkers associated with hepatocytes, (HNF4, albumin, HEPPAR3, etc.). They are seen surrounding cells ranging in size from small to typical hepatocytes, and with a gradient of expression of cholangiocyte-associated biomarkers (e.g. EpCAM) decreasing from the periphery to the center (Regenerative Clusters: see Figure 1). It is not clear in FHF whether cholangiocytes give rise to hepatocytes or vice versa. Most cells in liver tissues from patients with FHF, however, are typical cholangiocytes, so it is likely that these are the source of hepatocytes detected in the (more rarely seen) regenerative clusters. The term “progenitor” cells (used in tissue biology to describe the immediate progeny of stem cells) is most often used to collectively cover these proliferating cells with mixed hepatobiliary biomarkers in rats, mice, humans and fish. This may be inappropriate because it implies that such cells are generated by tissue-specific stem cells, even though such stem cells are not identifiable in the liver. Though the term “progenitor cells” does not fulfill criteria used in other tissues, it does imply a transition from one type of cell differentiation to another. Thus, the term has persisted in hepatic biology, even though it is not entirely appropriate. However, in most of the scenarios below, hepatocytes and cholangiocytes appear to function as “facultative stem cells” for each other. Thus the ter...

Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology

“…An alternative, although not exclusive, theory against the existence of a dedicated population of LPCs proposes that BECs and hepatocytes function as facultative stem cells, or differentiated cells that may function as stem cells after injury (152). Therefore, BECs transdifferentiate to hepatocytes, and vice versa, to mediate liver regeneration.…”

Two Fresh Streams to Fill the Liver’s Hepatocyte Pool

“…Their ready proliferation following partial hepatectomy or growth factor administration suggests that they may, but this requires dedicated lineage tracing to prove or disprove. To add to this abundance of regenerative sources, the biliary ductules also appear capable of hepatocyte regeneration following severe liver injury when hepatocyte senescence develops (Lu et al, 2015;Michalopoulos and Khan, 2015).…”

Making It New Again

“…This response has recently been elegantly investigated in zebrafish (Choi et al, 2014; He et al, 2014). Some evidence shows that parenchymal cells can be induced to transdifferentiate to regenerate functional hepatocytes (Michalopoulos and Khan, 2015), yet it is unclear whether this mechanism of regeneration is conserved across species.…”

“…If the liver suffers widespread damage and hepatocyte proliferation is limited or if the hepatocytes loss is so massive that the remaining cells cannot adequately and quickly repopulated the liver, an alternative mechanism to regenerate lost mass is activated: bi-potential liver progenitor cells that can differentiate into both cells of the biliary and the hepatic lineage (i.e. oval cells in mammals) are activated to repopulate the liver (Michalopoulos and Khan, 2015). In this scenario, liver regeneration is dictated not only on hepatocyte proliferation but also on the degree of continuous cell death, on the extent of fibrosis, which may physically restrain liver growth, and on the ability to mobilize progenitor cells.…”