Preexisting epithelial diversity in normal human livers: A tissue-tethered cytometric analysis in portal/periportal epithelial cells

Isse, Kumiko; Lesniak, Andrew; Grama, Kedar; Maier, J C; Specht, Susan; Castillo-Rama, Marcela; Lunz, John G.; Roysam, Badrinath; Michalopoulos, George K.; Demetris, Anthony J.

doi:10.1002/hep.26131

Cited by 41 publications

(46 citation statements)

References 41 publications

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“…Similar signals were detected in liver sections from WT mice (Figure S5C). Normal human liver contains periportal hepatocytes that co-express HNF4α and HNF1β (Isse et al, 2013). Importantly, hSOX9 and hOPN were expressed by some periportal hepatocytes in human liver (Figure 5F), suggesting that human liver also contains HybHP.…”

Section: Resultsmentioning

confidence: 99%

Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer

Font-Burgada

Shalapour

Ramaswamy

et al. 2015

Cell

416

428

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SUMMARY Compensatory proliferation triggered by hepatocyte loss is required for liver regeneration and maintenance but also promotes development of hepatocellular carcinoma (HCC). Despite extensive investigation, the cells responsible for hepatocyte restoration or HCC development remain poorly characterized. We used genetic lineage tracing to identify cells responsible for hepatocyte replenishment following chronic liver injury and queried their roles in three distinct HCC models. We found that a pre-existing population of periportal hepatocytes, located in the portal triads of healthy livers and expressing low amounts of Sox9 and other bile-duct-enriched genes, undergo extensive proliferation and replenish liver mass after chronic hepatocyte-depleting injuries. Despite their high regenerative potential, these so-called hybrid hepatocytes do not give rise to HCC in chronically injured livers and thus represent a unique way to restore tissue function and avoid tumorigenesis. This specialized set of pre-existing differentiated cells may be highly suitable for cell-based therapy of chronic hepatocyte-depleting disorders.

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Section: Resultsmentioning

confidence: 99%

Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer

Font-Burgada

Shalapour

Ramaswamy

et al. 2015

Cell

416

428

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“…Because liver regeneration is usually contingent on the proliferation of hepatocytes, it has been proposed that when hepatocyte proliferation is impaired, bipotent LPCs proliferate and differentiate into hepatocytes to mediate liver regeneration (86, 135) (Figure 7 a ). LPCs are not detected in normal livers (136) and are thought to arise from cells in the canal of Hering (131, 135, 137), the hepatocyte-biliary interface of bile canaliculi and terminal bile ducts, which contains small hepatocytes with the expression of both BEC-marker cytokeratin 19 and albumin (137) and BECs with the expression of hepatocyte markers such as HNF4α (138). Many studies have demonstrated that LPCs are derived from BECs using the choline-deficient, ethionine-supplemented (CDE) diet, a model of liver injury that promotes expansion of LPCs (139).…”

Section: Cell Type–specific Roles Of Wnt/β-catenin Signaling In Livermentioning

confidence: 99%

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

Russell

Monga

2018

Annu. Rev. Pathol. Mech. Dis.

346

282

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The liver is an organ that performs a multitude of functions, and its health is pertinent and indispensable to survival. Thus, the cellular and molecular machinery driving hepatic functions is of utmost relevance. The Wnt signaling pathway is one such signaling cascade that enables hepatic homeostasis and contributes to unique hepatic attributes such as metabolic zonation and regeneration. The Wnt/β-catenin pathway plays a role in almost every facet of liver biology. Furthermore, its aberrant activation is also a hallmark of various hepatic pathologies. In addition to its signaling function, β-catenin also plays a role at adherens junctions. Wnt/β-catenin signaling also influences the function of many different cell types. Due to this myriad of functions, Wnt/β-catenin signaling is complex, context-dependent, and highly regulated. In this review, we discuss the Wnt/β-catenin signaling pathway, its role in cell-cell adhesion and liver function, and the cell type–specific roles of Wnt/β-catenin signaling as it relates to liver physiology and pathobiology.

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“…Cholangiocytes at the end of the canals of Hering, in sites with immediate proximity to hepatocytes, have mixed expression of transcription factors 7 . LPC might also derive from pre-existing hepatic tissue-specific stem cells.…”

Section: Possible Origins Of Lpcmentioning

confidence: 99%

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

2015

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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...

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Preexisting epithelial diversity in normal human livers: A tissue-tethered cytometric analysis in portal/periportal epithelial cells

Cited by 41 publications

References 41 publications

Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer

Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer

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

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

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