Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration

Abstract

Niches containing stem/progenitor cells are present in different anatomical locations along the human biliary tree and within liver acini. The most primitive stem/progenitors, biliary tree stem/progenitor cells (BTSCs), reside within peribiliary glands located throughout large extrahepatic and intrahepatic bile ducts. BTSCs are multipotent and can differentiate towards hepatic and pancreatic cell fates. These niches' matrix chemistry and other characteristics are undefined. Canals of Hering (bile ductules) are found periportally and contain hepatic stem/progenitor cells (HpSCs), participating in the renewal of small intrahepatic bile ducts and being precursors to hepatocytes and cholangiocytes. The niches also contain precursors to hepatic stellate cells and endothelia, macrophages, and have a matrix chemistry rich in hyaluronans, minimally sulfated proteoglycans, fetal collagens, and laminin. The microenvironment furnishes key signals driving HpSC activation and differentiation. Newly discovered third niches are pericentral within hepatic acini, contain Axin2+ unipotent hepatocytic progenitors linked on their lateral borders to endothelia forming the central vein, and contribute to normal turnover of mature hepatocytes. Their relationship to the other stem/progenitors is undefined. Stem/progenitor niches have important implications in regenerative medicine for the liver and biliary tree and in pathogenic processes leading to diseases of these tissues.

Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver

“…28 The structures we have reported are very similar to structures recently reviewed in a report that focused on the hepatic niche and the presence of Hepatic Stem Cells (HpSCs) in "reactive ductules." 28 In Fig. 4A of that report, HpSCs that are CK7+ and Sox9+ are identified at the edge of reactive ductules.…”

“…In a recent review, 28 the liver stem cell niche is examined in great detail, and structures are identified in severely diseased livers that greatly resemble those in this report. Two markers of stem progenitor cells that were reviewed and identified in ductular structures in the diseased livers were CK7 and Sox-9.…”

“…Two markers of stem progenitor cells that were reviewed and identified in ductular structures in the diseased livers were CK7 and Sox-9. 28 In pluripotent stem cells, additional markers are expressed before hepatic lineage specification and commitment, for example, OCT4, stage-specific embryonic antigens (SSEAs), 36,37 and thus, we incorporated OCT4 expression analysis in our studies. Moreover, we examined whether specific microRNAs (miRNA), which play roles in liver differentiation, 38,39 could be identified within stem/progenitor lineages or in adjacent cells to illuminate further differentiation mechanisms.…”

Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions

“…HOCs are bipotent and able to further mature to hepatocytes or cholangiocytes when there is injury causing loss of hepatocytes or cholangiocytes, especially under a condition in which hepatocellular proliferation is inhibited, 25 and so do small hepatocyte-like cells in a scenario of pre-treatment with retrorsine before partial hepatectomy. 26 One study indicated that bone morrow cells may migrate into injured liver to become the source of oval cells. 27 In human liver, ductular epithelial cells, 28 or primitive hepatic stem cells 29 and EpCAM-positive cells are believed in a progenitor cell compartment.…”

The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications

“…HPCs minimally contribute to the normal turnover of liver parenchymal cells but are activated in the context of liver injuries [103]. The activation of HPCs is sustained by a specialized niche that furnishes several key signals driving HPC activity [104]. In normal conditions, HPCs are surrounded by endothelial cells, HSCs, and KCs, which release paracrine signals for the maintenance of the stem/progenitors in a quiescent state.…”