Hepatic progenitor cells in human liver diseases

doi:10.1016/S1084952102001258

Seminars in Cell & Developmental Biology

Volume 13, Issue 6, December 2002, Pages 389-396

https://doi.org/10.1016/S1084952102001258 Get rights and content

Abstract

The canals of Hering and bile ductules in human liver contain hepatic progenitor cells that can differentiate towards the biliary and hepatocytic lineage. Proliferation and differentiation of hepatic progenitor cells is referred to as ‘activation’ and this process occurs to a variable degree in almost all human liver diseases. Several studies indicate that hepatic progenitor cell activation in diseased liver is regulated by neural and neuroendocrine factors such as the vagal innervation. Analogous to oval cells in animal liver, there is evidence that human hepatic progenitor cells may be able to give rise to hepatocellular carcinoma and other liver tumors.

Section snippets

Hepatic progenitor cells in human liver: localization, phenotype and comparison to animal liver

Hepatic progenitor cells (HPCs) are small epithelial cells with an oval nucleus and scant cytoplasm. They were firstly described in rat liver and the shape of their nucleus inspired Farber¹ to coin them ‘oval cells’. This name has since then consistently been used for HPCs in animal liver. It has been shown in both animal and human liver that HPCs are bipotential cells that can differentiate towards the biliary and the hepatocytic lineage.2., 3., 4., 5., 6., 7., 8. Differentiation towards

Activation of human hepatic progenitor cells

‘Activation’ of HPCs or oval cells is a term which is used to refer to an increase in the number of HPCs and differentiation of the HPCs towards the biliary and/or hepatocytic lineage.23., 24. HPC activation only takes place when damage and loss of hepatocytes and/or cholangiocytes is combined with impaired regeneration of the mature cell type involved.²⁵ Since almost all human liver diseases are characterized by a certain degree of damage, loss and impaired regeneration of hepatocytes and/or

The role of hepatic progenitor cells in tumor development in animal and human liver

It has been thought for a long time that the mature hepatocyte represents the cell of origin of all hepatocellular carcinomas (HCCs). The results of several studies performed in recent years indicate that this concept is not correct. In a number of animal models of hepatocarcinogenesis, the development of HCC is preceded by oval cell activation and the HCCs in these animal models express oval cell marker such as OV-6 and alpha-fetoprotein.39., 57., 58., 59. This indicates that oval cells

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Cited by (179)

Specific knockdown of Y-box binding protein 1 in hepatic progenitor cells inhibits proliferation and alleviates liver fibrosis
2022, European Journal of Pharmacology
Citation Excerpt :
It is unclear why collagen deposition occurs in the portal areas, whereas damage occurs in the lobular sites. Recent studies suggested that DR caused by the expansion of HPCs plays an important role in periportal fibrosis, although it remains controversial whether DR causes collagen deposition or collagen deposition causes DR (Glaser et al., 2009; Libbrecht and Roskams, 2002; Sato et al., 2019). In clinical research, Gadd et al. (2014) found that HPC proliferation is related to the degree of the inflammatory response and indirectly promoted the development of fibrosis in 33 patients with NAFLD (Gadd et al., 2014).
The proliferation of hepatic progenitor cells (HPCs) contributes to liver regeneration and fibrogenesis during chronic liver injury; however, the mechanism modulating HPC proliferation remains unknown. Y-box binding protein-1 (YB-1) is a transcription factor that regulates the transcription of several genes and is highly expressed in liver injury. We explored the role of YB-1 in HPC proliferation and liver fibrosis. We detected increased expansion of HPCs and elevated levels of YB-1 in HPCs from patients with hepatitis B virus-related fibrosis and choline-deficient ethionine-supplemented or 5-diethoxycarbonyl-1,4-dihydrocollidine diet-induced mice compared with those in control groups. HPC-specific deletion of YB-1 using YB-1^flox/flox; Foxl1-Cre^+/- mice led to reduced HPC expansion and less collagen deposition in the liver tissues compared with that in Cre^-/- mice. In cultured primary HPCs, YB-1 knockdown inhibited HPC proliferation. Further experiments indicated YB-1 negatively regulated p53 expression, and silencing of p53 blocked YB-1 knockdown-mediated inhibition of HPC proliferation. Collectively, YB-1 negatively regulates HPC proliferation and alleviates liver fibrosis by p53.
New insights on the role of vascular endothelial growth factor in biliary pathophysiology
2021, JHEP Reports
The family of vascular endothelial growth factors (VEGFs) includes 5 members (VEGF-A to -D, and placenta growth factor), which regulate several critical biological processes. VEGF-A exerts a variety of biological effects through high-affinity binding to tyrosine kinase receptors (VEGFR-1, -2 and -3), co-receptors and accessory proteins. In addition to its fundamental function in angiogenesis and endothelial cell biology, VEGF/VEGFR signalling also plays a role in other cell types including epithelial cells. This review provides an overview of VEGF signalling in biliary epithelial cell biology in both normal and pathologic conditions. VEGF/VEGFR-2 signalling stimulates bile duct proliferation in an autocrine and paracrine fashion. VEGF/VEGFR-1/VEGFR-2 and angiopoietins are involved at different stages of biliary development. In certain conditions, cholangiocytes maintain the ability to secrete VEGF-A, and to express a functional VEGFR-2 receptor. For example, in polycystic liver disease, VEGF secreted by cystic cells stimulates cyst growth and vascular remodelling through a PKA/RAS/ERK/HIF1α-dependent mechanism, unveiling a new level of complexity in VEFG/VEGFR-2 regulation in epithelial cells. VEGF/VEGFR-2 signalling is also reactivated during the liver repair process. In this context, pro-angiogenic factors mediate the interactions between epithelial, mesenchymal and inflammatory cells. This process takes place during the wound healing response, however, in chronic biliary diseases, it may lead to pathological neo-angiogenesis, a condition strictly linked with fibrosis progression, the development of cirrhosis and related complications, and cholangiocarcinoma. Novel observations indicate that in cholangiocarcinoma, VEGF is a determinant of lymphangiogenesis and of the immune response to the tumour. Better insights into the role of VEGF signalling in biliary pathophysiology might help in the search for effective therapeutic strategies.
Hepatic Stem/Progenitor Cell Activation Differs between Primary Sclerosing and Primary Biliary Cholangitis
2018, American Journal of Pathology
Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are human primary cholangiopathies characterized by the damage of mature cholangiocytes and by the appearance of ductular reaction (DR) as the results of hepatic progenitor cell activation. This study evaluated the differences in progenitor cell niche activation between these two cholangiopathies. Liver tissue was obtained from healthy liver donors (n = 5) and from patients with PSC (n = 20) or PBC (n = 20). DR, progenitor cell phenotype, and signaling pathways were investigated by IHC analysis and immunofluorescence. Our results indicated that DR was more extended, appeared earlier, and had a higher proliferation index in PBC compared with PSC. In PBC, DR was strongly correlated with clinical prognostic scores. A higher percentage of sex determining region Y–box (SOX)9⁺ and cytokeratin 19⁺ cells but fewer features of hepatocyte fate characterized progenitor cell activation in PBC versus PSC. Lower levels of laminin and neurogenic locus notch homolog protein 1 but higher expression of wingless-related integration site (WNT) family pathway components characterize progenitor cell niche in PSC compared with PBC. In conclusion, progenitor cell activation differs between PSC and PBC and is characterized by a divergent fate commitment and different signaling pathway predominance. In PBC, DR represents a relevant histologic prognostic marker.
Hepatic Progenitor Cells: An Update
2017, Gastroenterology Clinics of North America
“Small Hepatocytes” in the Liver
2023, Cells
Systematic review of cholangiocarcinoma in Africa: epidemiology, management, and clinical outcomes
2023, BMC Gastroenterology

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Hepatic progenitor cells in human liver diseases

Abstract

Section snippets

Hepatic progenitor cells in human liver: localization, phenotype and comparison to animal liver

Activation of human hepatic progenitor cells

The role of hepatic progenitor cells in tumor development in animal and human liver

Hepatology

J. Hepatol.

Hepatology

Hum. Pathol.

Pathol. Res. Pract.

J. Hepatol.

Am. J. Pathol.

Differentiation

Am. J. Pathol.

Am. J. Pathol.

Curr. Opin. Cell Biol.

Mod. Pathol.

Am. J. Pathol.

Liver Transpl.

Am. J. Pathol.

Biochem. Biophys. Res. Commun.

Hepatology

Gastroenterology

Hepatology

J. Hepatol.

J. Hepatol.

J. Hepatol.

Exp. Mol. Pathol.

Hum. Pathol.

Biochem. Biophys. Res. Commun.

J. Hepatol.

J. Hepatol.

Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylaminofluorene and 3′-methyl-4-dimethylaminoazobenzene

Cancer Res.

Identification of bipotential progenitor cells in human liver regeneration

Lab. Invest.

Precursor-product relationship between oval cells and hepatocytes: comparison between tritiated thymidine and bromodeoxyuridine as tracers

Carcinogenesis

The canals of Hering and hepatic stem cells in humans

Hepatology

Intraseptal hepatocytes in cirrhosis: evidence for regeneration from stem cells

Mod. Pathol.

Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury

Hepatology

A cytokeratin-immunohistochemical study of focal nodular hyperplasia of the liver: further evidence that ductular metaplasia of hepatocytes contributes to ductular ‘proliferation’

Liver

Microanatomy of the human liver-exploring the hidden interfaces

Hepatology

Ultrastructural characteristics of novel epithelial cell types identified in human pathologic liver specimens with chronic ductular reaction

Am. J. Pathol.

‘Undifferentiated progenitor cells’ in focal nodular hyperplasia of the liver

Histopathology

Small epithelial cells in extrahepatic biliary atresia: electron microscopic and immunoelectron microscopic findings suggest a close relationship to liver progenitor cells

Histopathology