Role Of Hepatic Progenitor Cells Research Articles

Correlation between Cancer Stem Cells, Inflammation and Malignant Transformation in a DEN-Induced Model of Hepatic Carcinogenesis.

Chronic inflammation and cancer stem cells are known risk factors for tumorigenesis. The aetiology of hepatocellular carcinoma (HCC) involves a multistep pathological process that is characterised by chronic inflammation and hepatocyte damage, but the correlation between HCC, inflammation and cancer stem cells remains unclear. In this study, we examined the role of hepatic progenitor cells in a mouse model of chemical-induced hepatocarcinogenesis to elucidate the relationship between inflammation, malignant transformation and cancer stem cells. We used diethylnitrosamine (DEN) to induce liver tumour and scored for H&E and reticulin staining. We also scored for immunohistochemistry staining for OV-6 expression and analysed the statistical correlation between them. DEN progressively induced inflammation at week 7 (40%, 2/5); week 27 (75%, 6/8); week 33 (62.5%, 5/8); and week 50 (100%, 12/12). DEN progressively induced malignant transformation at week 7 (0%, 0/5); week 27 (87.5%, 7/8); week 33 (100%, 8/8); and week 50 (100%, 12/12). The obtained data showed that DEN progressively induced high-levels of OV-6 expression at week 7 (20%, 1/5); week 27 (37.5%, 3/8); week 33 (50%, 4/8); and week 50 (100%, 12/12). DEN-induced inflammation, malignant transformation and high-level OV-6 expression in hamster liver, as shown above, as well as applying Spearman’s correlation to the data showed that the expression of OV-6 was significantly correlated to inflammation (p = 0.001) and malignant transformation (p < 0.001). There was a significant correlation between the number of cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis in the hamster.

Hepatic progenitor cells promote the repair of schistosomiasis liver injury by inhibiting IL-33 secretion in mice

BackgroundHepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent or quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remains unknown.MethodsIn this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in the mice model of S. japonicum infection at different infectious stages. For validating the role of HPCs in hepatic injury, tumor necrosis factor-like-weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs in wild-type and IL-33−/− mice infected with S. japonicum.ResultsWe found that the proliferation of HPCs was accompanied by inflammatory granulomas and fibrosis formation. HPCs expansion promoted liver regeneration and inhibited inflammatory egg granulomas, as well as the deposition of fibrotic collagen. Interestingly, the expression of IL-33 was negatively associated with HPCs’ expansion. There were no obvious differences of liver injury caused by infection between wild-type and IL-33−/− mice with HPCs’ expansion. However, liver injury was more attenuated in IL-33−/− mice than wild-type mice when the proliferation of HPCs was inhibited by anti-TWEAK.ConclusionsOur data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33-dependent manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.

The role of hepatic progenitor cells in predicting response to therapy in Egyptian patients with chronic hepatitis C, genotype 4

Abstract Background Interferon therapy is used as a line of treatment of chronic hepatitis C virus (HCV) in several areas of the world including Egypt. Objective Our aim is to investigate the value of hepatic progenitor cells (HPCs) in predicting response of patients with chronic HCV, genotype 4 to pegylated interferon (PEGIFN) plus ribavirin (RBV) therapy. Methods Pretreatment liver biopsies obtained from 110 patients with chronic HCV, genotype 4 were examined immunohistochemically for HPCs using cytokeratin 19. The mean number of HPCs as ductular reaction (DR) and as isolated progenitor cells (IPCs) was counted in each case. The patients were classified into: those with sustained virological response (SVR) and those who did not achieve SVR. The results were compared between the two groups. Also, the relationships between HPCs and other clinico-pathologic variables were estimated using multivariate analysis. Results The mean number of HPCs was the only independent predictor of therapeutic response, being significantly higher in non-responders (P = 0 for DR and P = 0.03 for IPCs). On the other hand, fibrosis stage and steatosis were the only independent factors which showed a significant direct association with the mean number of HPCs in the form of DR and IPCs (P = 0 for each). Conclusion The number of HPCs provides prognostic information in chronic HCV since it is significantly associated with stage of fibrosis. More importantly, it can be used as a marker to predict response of patients with chronic HCV to PEGIFN plus RBV therapy.

Understanding the marvels behind liver regeneration.

Tissue regeneration is a process by which the remaining cells of an injured organ regrow to offset the missed cells. This field is relatively a new discipline that has been a focus of intense research by clinicians, surgeons, and scientists for decades. It constitutes the cornerstone of tissue engineering, creation of artificial organs, and generation and utilization of therapeutic stem cells to undergo transformation to different types of mature cells. Many medical experts, scientists, biologists, and bioengineers have dedicated their efforts to deeply comprehend the process of liver regeneration, striving for harnessing it to invent new therapies for liver failure. Liver regeneration after partial hepatectomy in rodents has been extensively studied by researchers for many years. It is divided into three important distinctive phases including (a) Initiation or priming phase which includes an overexpression of specific genes to prepare the liver cells for replication, (b) Proliferation phase in which the liver cells undergo a series of cycles of cell division and expansion and finally, (c) termination phase which acts as brake to stop the regenerative process and prevent the liver tissue overgrowth. These events are well controlled by cytokines, growth factors, and signaling pathways. In this review, we describe the function, embryology, and anatomy of human liver, discuss the molecular basis of liver regeneration, elucidate the hepatocyte and cholangiocyte lineages mediating this process, explain the role of hepatic progenitor cells and elaborate the developmental signaling pathways and regulatory molecules required to procure a complete restoration of hepatic lobule. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Signaling Pathways > Global Signaling Mechanisms Gene Expression and Transcriptional Hierarchies > Cellular Differentiation.

The role of hepatic progenitor cells in predicting response to therapy in Egyptian patients with chronic hepatitis C, genotype 4.

Interferon therapy is used as a line of treatment of chronic hepatitis C virus (HCV) in several areas of the world including Egypt. Our aim was to investigate the value of hepatic progenitor cells (HPCs) in predicting response of patients with chronic HCV, genotype 4 to pegylated interferon (PEGIFN) plus ribavirin (RBV) therapy. Pre-treatment liver biopsies obtained from 110 patients with chronic HCV, genotype 4 were examined immunohistochemically for HPCs using cytokeratin19. The mean number of HPCs as ductular reaction (DR) and as isolated progenitor cells (IPCs) was counted in each case. The patients were classified into: those with sustained virological response (SVR) and those who did not achieve SVR. The results were compared between the two groups. Also, the relationships between HPCs and other clinico-pathologic variables were estimated using multivariate analysis. The mean number of HPCs was the only independent predictor of therapeutic response, being significantly higher in non-responders (P = 0 for DR and P = 0.03 for IPCs). On the other hand, fibrosis stage and steatosis were the only independent factors which showed a significant direct association with the mean number of HPCs in the form of DR and IPCs (P = 0 for each). The number of HPCs provides prognostic information in chronic HCV since it is significantly associated with stage of fibrosis. More importantly, it can be used as a marker to predict response of patients with chronic HCV to PEGIFN plus RBV therapy.

RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers

Hepatic progenitor cells (HPCs) are small cells with a relative large oval nucleus and a scanty cytoplasm situated in the canals of Hering that express markers of (immature) hepatocytes and cholangiocytes. HPCs are present in large numbers in alcoholic steatohepatitis (ASH), one of the leading causes of chronic liver disease. To date, the mechanisms responsible for proliferation and differentiation of human HPCs are still poorly understood and the role of HPCs in ASH development is unknown. In this study, we aimed to characterise human HPCs and their interactions with other cells through comparison, on both protein and RNA level, of HPC-enriched cell populations from adult human liver tissue using different isolation methods. Fresh human liver tissue was collected from ASH explant livers and HPC-enriched cell populations were obtained via four different isolation methods: side population (SP), epithelial cell adhesion molecule (EpCAM) and trophoblast antigen 2 (TROP-2) membrane marker isolation and laser capture microdissection. Gene expression profiles of fluorescent-activated cell-sorted HPCs, whole liver extracts and laser microdissected HPC niches were determined by RNA-sequencing. Immunohistochemical evaluation of the isolated populations indicated the enrichment of HPCs in the SP, EpCAM+ and TROP-2+ cell populations. Pathway analysis of the transcription profiles of human HPCs showed an enrichment and activation of known HPC pathways like Wnt/β-catenin, TWEAK and HGF. Integration of the HPC niche profile suggests autocrine signalling by HPCs (TNFα, PDGFB and VEGFA) as well as paracrine signalling from the surrounding niche cells including MIF and IGF-1. In addition, we identified IL-17 A signalling as a potentially novel pathway in HPC biology. In conclusion, we provide the first RNA-seq-based, comparative transcriptome analysis of isolated human HPCs from ASH patients and revealed active signalling between HPCs and their surrounding niche cells in ASH livers and suggest that HPCs can actively contribute to liver inflammation.

Hepatic progenitor cells in canine and feline medicine: potential for regenerative strategies.

New curative therapies for severe liver disease are urgently needed in both the human and veterinary clinic. It is important to find new treatment modalities which aim to compensate for the loss of parenchymal tissue and to repopulate the liver with healthy hepatocytes. A prime focus in regenerative medicine of the liver is the use of adult liver stem cells, or hepatic progenitor cells (HPCs), for functional recovery of liver disease. This review describes recent developments in HPC research in dog and cat and compares these findings to experimental rodent studies and human pathology. Specifically, the role of HPCs in liver regeneration, key components of the HPC niche, and HPC activation in specific types of canine and feline liver disease will be reviewed. Finally, the potential applications of HPCs in regenerative medicine of the liver are discussed and a potential role is suggested for dogs as first target species for HPC-based trials.

Role of Hepatic Progenitor Cells in Nonalcoholic Fatty Liver Disease Development: Cellular Cross-Talks and Molecular Networks

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis, (NASH) which may progress to cirrhosis and hepatocellular carcinoma. NASH has been independently correlated with atherosclerosis progression and cardiovascular risk. NASH development is characterized by intricate interactions between resident and recruited cells that enable liver damage progression. The increasing general agreement is that the cross-talk between hepatocytes, hepatic stellate cells (HSCs) and macrophages in NAFLD has a main role in the derangement of lipid homeostasis, insulin resistance, danger recognition, immune tolerance response and fibrogenesis. Moreover, several evidences have suggested that hepatic stem/progenitor cell (HPCs) activation is a component of the adaptive response of the liver to oxidative stress in NAFLD. HPC activation determines the appearance of a ductular reaction. In NASH, ductular reaction is independently correlated with progressive portal fibrosis raising the possibility of a periportal fibrogenetic pathway for fibrogenesis that is parallel to the deposition of subsinusoidal collagen in zone 3 by HSCs. Recent evidences indicated that adipokines, a class of circulating factors, have a key role in the cross-talk among HSCs, HPCs and liver macrophages. This review will be focused on cellular cross-talk and the relative molecular networks which are at the base of NASH progression and fibrosis.

Classification of primary hepatic tumours in the dog

Many advances have been made in the characterisation of primary liver tumours in humans, in particular relating to the identification and role of hepatic progenitor cells, resulting in a new classification. The aim of the present study was to investigate the presence and relative frequency of morphological types of canine primary hepatic neoplasms and to determine whether a classification similar to the human scheme can be applied to these canine neoplasms. Canine primary liver tumours (n=106) were examined histologically and with the immunohistochemical markers keratin 19, HepPar-1, epithelial membrane antigen/mucin-1, CD10, neuron-specific enolase and chromogranin-A. Eleven nodular hyperplasias and 82 tumours of hepatocellular origin were diagnosed. The latter were subdivided in hepatocellular tumours with 0–5% positivity for K19 (n=62), which were well differentiated and had no evidence of metastasis, tumours with >5% positivity for K19 (n=17), which were poorly differentiated and had intrahepatic and/or distant metastasis, and a scirrhous subgroup (n=3) with an intermediate position with regard to K19 staining and malignancy. Ten cholangiocellular tumours (nine cholangiocellular carcinomas and one cholangiolocarcinoma) were diagnosed and all had intrahepatic and/or distant metastases. Three neuroendocrine carcinomas were also diagnosed. Histopathological and immunohistochemical examination of canine primary hepatic neoplasms can differentiate hepatocellular, cholangiocellular and neuroendocrine tumours, in accordance with the most recent human classification system.

2 A NOVEL INDUCIBLE GENETIC MURINE MODEL OF HEPATOCYTE SENESCENCE CAUSES A MASSIVE HEPATIC OVAL CELL RESPONSE AND COMPLETE HEPATOCYTE REPLACEMENT FROM ENDOGENOUS PROGENITOR CELLS

Background and aims: In severe advanced liver disease it is increasingly recognised that hepatic progenitor cells (HPCs) are a major source of parenchymal regeneration but may also be a cellular source of liver cancers. Murine liver injury models eliciting HPC activation frequently demonstrate relatively small and heterogeneous activation of HPCs, together with simultaneous hepatocyte proliferation. While purified HPCs from such models have been shown in transplant models to repopulate injured liver the full repopulation potential of endogenous HPC remains unclear. In order to investigate the role of HPCs directly it is necessary to specifically inhibit hepatocyte proliferation. Mdm2 is a key inhibitor of the tumour suppressor gene p53. P53 activation results in cell cycle arrest, therefore hepatocyte specific Mdm2 knockout using Cre Lox technology provides an opportunity to investigate HPC mediated liver regeneration. Methods: Hepatocyte specific loss of Mdm2 was achieved by i.p. administration of β-naphthoflavone to AhCre+ Mdm2fl/fl mice. Immunohistochemical analysis was performed for p21, p53, and the HPC marker panCK. Cellular proliferation was assessed using Ki67 and BrdU label incorporation. Serum was analysed for LFTs. Results: Hepatocytes, but not other non parenchymal hepatic cells, are p53hi and p21hi following induction of Mdm2 loss by recombination. Loss of hepatocyte proliferation and massive expansion of p53low HPCs rapidly occurs. This results in the production of phenotypically normal p53low/p21low hepatocytes and the restoration of normal liver function. PanCK+ progenitor cell expansion is over three times greater than is seen in CDE diet induced HPC expansion (Mean±SEM; Mdm2 212± 27.48 versus CDE 60.89 ± 17.59 versus control 13.85± 0.82). No cancers or significant fibrosis are observed following complete replacement of the hepatic parenchyma during long term follow up. Conclusions: Mdm2 knockout induces hepatocyte senescence and induces massive expansion of p53low HPCs resulting in complete regeneration of the liver parenchyma in the absence of long term sequelae. This novel model permits detailed examination of HPC mediated regeneration and demonstrates the physiological potential of HPCs and highlights their therapeutic potential.