Hepatic stem cell niches

Abstract

Stem cell niches are special microenvironments that maintain stem cells and control their behavior to ensure tissue homeostasis and regeneration throughout life. The liver has a high regenerative capacity that involves stem/progenitor cells when the proliferation of hepatocytes is impaired. In recent years progress has been made in the identification of potential hepatic stem cell niches. There is evidence that hepatic progenitor cells can originate from niches in the canals of Hering; in addition, the space of Disse may also serve as a stem cell niche during fetal hematopoiesis and constitute a niche for stellate cells in adults.

Figure 1. Model of the hepatic stem cell niche in the canals of Hering.

Label-retaining cells (black nuclei) represent putative stem cells and are located in the canals of Hering as keratin-expressing cells. Also, cholangiocytes of intralobular bile ducts, small hepatocytes, and less-characterized null cells retain the BrdU label after acetaminophen treatment of mice (50). Coexpression of keratin 19 and albumin in small hepatocytes at the interface of cholangiocytes and hepatocytes in the canals of Hering indicate that hepatocytes are generated at this site by stem/progenitor cells (116). A continuous production of hepatocytes within the portal field is supported by SOX9 fate-mapping analysis (54). Small cholangiocytes lining the canals of Hering and ductules may represent cholangiocyte precursors, which potentially contribute to the cholangiocyte population of larger bile ducts (116) and could explain the presence of label-retaining cholangiocytes at this site (50).

Figure 2. Model of intercellular communication in the stellate cell niche of normal liver.

Hepatic stellate cells (HSCs) are located on basement membrane proteins such as laminin and collagen type IV (grid) between LSECs and parenchymal cells (PCs). HSCs are attracted to LSECs through CXCL12 and are associated with PCs, which express Notch ligands such as jagged 1 (JAG1) and release canonical WNT ligands to influence stellate cell development (72). Quiescent stellate cells in turn secrete HGF, which is probably involved in liver tissue homeostasis and can support hepatic progenitor cells (75, 76). HSCs receive signals from the sympathetic nervous system through norepinephrine (NE) release (112, 115).