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Cholangiocyte hepatocyte

Adil El Taghdouini, Leo A van Grunsven
Chronic liver injury to hepatocytes or cholangiocytes, when left unmanaged, leads to the development of liver fibrosis, a condition characterized by the excessive intrahepatic deposition of extracellular matrix proteins. Activated hepatic stellate cells constitute the predominant source of extracellular matrix in fibrotic livers and their transition from a quiescent state during fibrogenesis is associated with important alterations in their transcriptional and epigenetic landscape. Areas covered: We briefly describe the processes involved in hepatic stellate cell activation and discuss our current understanding of alterations in the epigenetic landscape, i...
October 20, 2016: Expert Review of Gastroenterology & Hepatology
Masakazu Sugiyama, Tomoharu Yoshizumi, Yoshihiro Yoshida, Yuki Bekki, Yoshihiro Matsumoto, Shohei Yoshiya, Takeo Toshima, Toru Ikegami, Shinji Itoh, Norifumi Harimoto, Shinji Okano, Yuji Soejima, Ken Shirabe, Yoshihiko Maehara
Autophagy is a homeostatic process regulating turnover of impaired proteins and organelles, and p62 (sequestosome-1, SQSTM1) functions as the autophagic receptor in this process. p62 also functions as a hub for intracellular signaling such as that in the mammalian target of rapamycin (mTOR) pathway. Liver stem/progenitor cells have the potential to differentiate to form hepatocytes or cholangiocytes. In this study, we examined effects of autophagy, p62 and associated signaling on hepatic differentiation. Adult stem/progenitor cells were isolated from the liver of mice with chemically-induced liver injury...
October 17, 2016: Journal of Cellular Physiology
Maiko Terada, Kenichi Horisawa, Shizuka Miura, Yasuo Takashima, Yasuyuki Ohkawa, Sayaka Sekiya, Kanae Matsuda-Ito, Atsushi Suzuki
Intrahepatic cholangiocarcinoma (ICC) is a malignant epithelial neoplasm composed of cells resembling cholangiocytes that line the intrahepatic bile ducts in portal areas of the hepatic lobule. Although ICC has been defined as a tumor arising from cholangiocyte transformation, recent evidence from genetic lineage-tracing experiments has indicated that hepatocytes can be a cellular origin of ICC by directly changing their fate to that of biliary lineage cells. Notch signaling has been identified as an essential factor for hepatocyte conversion into biliary lineage cells at the onset of ICC...
October 4, 2016: Scientific Reports
Fei Chen, Hao Yao, Minjun Wang, Bing Yu, Qinggui Liu, Jianxiu Li, Zhiying He, Yi-Ping Hu
Induced hepatic stem cells (iHepSCs) have great potential as donors for liver cell therapy due to their abilities for self-renewal and bi-potential differentiation. However, the molecular mechanism regulating proliferation and differentiation of iHepSCs is poorly understood. In this study, we provide evidence that the homeodomain transcription factor, Pitx2, is essential to maintain iHepSCs stem cell characteristics. Suppressing Pitx2 expression in iHepSCs by lentivirus mediated specific shRNA markedly reduced the expression of the hepatic stem cell-associated genes (Lgr5, EpCAM, and Sox9) with concomitant inhibition of proliferation by blocking the G1/S phase transition, and these phenotypic changes were reversed upon re-expression of Pitx2...
September 30, 2016: International Journal of Biochemistry & Cell Biology
Ana Lleo, Zhaolian Bian, Haiyan Zhang, Qi Miao, Fang Yang, Yanshen Peng, Xiaoyu Chen, Ruqi Tang, Qixia Wang, Dekai Qiu, Jingyuan Fang, Cristina Sobacchi, Anna Villa, Luca Di Tommaso, Massimo Roncalli, M Eric Gershwin, Xiong Ma, Pietro Invernizzi
There is substantial data that suggests an abnormality of innate immunity in patients with primary biliary cholangitis (PBC) which includes the transcription factor nuclear factor-kB (NF-kB) and well as downstream inflammatory signaling pathways. In addition, ImmunoChip analysis has identified a novel PBC-associated locus near the receptor activator of NF-kB ligand (RANKL) gene. Based on these observations, we investigated the role of the RANKL axis in the liver of patients with PBC compared to controls. We used immunohistochemistry to quantitate liver expression of RANKL, its receptor (RANK), and importantly the decoy receptor osteoprotegerin (OPG), including a total of 122 liver samples (PBC = 37, primary sclerosing cholangitis = 20, autoimmune hepatitis = 26, chronic hepatitis B = 32 and unaffected controls = 7)...
2016: PloS One
Andrey Elchaninov, Timur Fatkhudinov, Natalia Usman, Evgeniya Kananykhina, Irina Arutyunyan, Andrey Makarov, Galina Bolshakova, Dmitry Goldshtein, Gennady Sukhikh
Proliferation of hepatocytes is known to be the main process in the hepatectomy-induced liver regrowth; however, in cases of extensive loss it may be insufficient for complete recovery unless supported by some additional sources e.g. mobilization of undifferentiated progenitors. The study was conducted on rat model of 80% subtotal hepatectomy; the objective was to evaluate contributions of hepatocytes and resident progenitor cells to the hepatic tissue recovery via monitoring specific mRNA and/or protein expression levels for a panel of genes implicated in growth, cell differentiation, angiogenesis, and inflammation...
2016: PloS One
Daniel Karin, Yukinori Koyama, David Brenner, Tatiana Kisseleva
Liver fibrosis results from chronic injury of hepatocytes and activation of Collagen Type I producing myofibroblasts that produce fibrous scar in liver fibrosis. Myofibroblasts are not present in the normal liver but rapidly appear early in experimental and clinical liver injury. The origin of the myofibroblast in liver fibrosis is still unresolved. The possibilities include activation of liver resident cells including portal fibroblasts, hepatic stellate cells, mesenchymal progenitor cells, and fibrocytes recruited from the bone marrow...
August 30, 2016: Differentiation; Research in Biological Diversity
Jasmin Svinka, Sandra Pflügler, Markus Mair, Hanns-Ulrich Marschall, Jan G Hengstler, Patricia Stiedl, Valeria Poli, Emilio Casanova, Gerald Timelthaler, Maria Sibilia, Robert Eferl
: We have demonstrated that the signal transducer and activator of transcription 3 (STAT3) protects from cholestatic liver injury. Specific ablation of STAT3 in hepatocytes and cholangiocytes (STAT3(∆hc)) aggravated liver damage and fibrosis in the Mdr2(-/-) (multidrug resistance 2) mouse model for cholestatic disease. Upregulation of bile acid biosynthesis genes and downregulation of epidermal growth factor receptor (EGFR) expression were observed in STAT3(∆hc) Mdr2(-/-) mice but the functional consequences of these processes in cholestatic liver injury remained unclear...
August 27, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Kyo-Sang Yoo, Woo Taek Lim, Ho Soon Choi
Cholangiocytes, the lining epithelial cells in bile ducts, are an important subset of liver cells. They are activated by endogenous and exogenous stimuli and are involved in the modification of bile volume and composition. They are also involved in damaging and repairing the liver. Cholangiocytes have many functions including bile production. They are also involved in transport processes that regulate the volume and composition of bile. Cholangiocytes undergo proliferation and cell death under a variety of conditions...
September 15, 2016: Gut and Liver
Qian Zhao, Wen-Long Yu, Xin-Yuan Lu, Hui Dong, Yi-Jin Gu, Xia Sheng, Wen-Ming Cong, Meng-Chao Wu
BACKGROUND: Combined hepatocellular and cholangiocarcinoma (CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its cellular origin remains unclear. The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC. METHODS: The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC (SHC)...
2016: Chinese Journal of Cancer
Hirohisa Okabe, Jing Yang, Kyle Sylakowski, Mladen Yovchev, Yoshitaka Miyagawa, Shanmugam Nagarajan, Maria Chikina, Michael Thompson, Michael Oertel, Hideo Baba, Satdarshan P Monga, Kari Nichole Nejak-Bowen
: Hepatic repair is directed chiefly by the proliferation of resident mature epithelial cells. Furthermore, if predominant injury is to cholangiocytes, the hepatocytes can transdifferentiate to cholangiocytes to assist in the repair and vice versa, as shown by various fate-tracing studies. However, the molecular bases of reprogramming remain elusive. Using two models of biliary injury where repair occurs through cholangiocyte proliferation and hepatocyte transdifferentiation to cholangiocytes, we identify an important role of Wnt signaling...
November 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Orit Goldman, Idan Cohen, Valerie Gouon-Evans
In the early fetal liver, hematopoietic progenitors expand and mature together with hepatoblasts, the liver progenitors of hepatocytes and cholangiocytes. Previous analyses of human fetal livers indicated that both progenitors support each other's lineage maturation and curiously share some cell surface markers including CD34 and CD133. Using the human embryonic stem cell (hESC) system, we demonstrate that virtually all hESC-derived hepatoblast-like cells (Hep cells) transition through a progenitor stage expressing CD34 and CD133 as well as GATA2, an additional hematopoietic marker that has not previously been associated with human hepatoblast development...
August 9, 2016: Stem Cell Reports
Yu Wang, Xueting Mei, Jingquan Yuan, Xiaofang Lai, Donghui Xu
Dietary intakes of taurine and zinc are associated with decreased risk of liver disease. In this study, solid dispersions (SDs) of a taurine zinc complex on hepatic injury were examined in vitro using the immortalized human hepatocyte cell line L02 and in a rat model of bile duct ligation. Sham-operated and bile duct ligated Sprague-Dawley rats were treated with the vehicle alone or taurine zinc (40, 80, 160mg/kg) for 17days. Bile duct ligation significantly increased blood lipid levels, and promoted hepatocyte apoptosis, inflammation and compensatory biliary proliferation...
July 29, 2016: Toxicology
Felipe Serrano, Maria García-Bravo, Marina Blazquez, Josema Torres, Jose V Castell, Jose C Segovia, Roque Bort
BACKGROUND: Several studies have reported the direct conversion of mouse fibroblasts to hepatocyte-like cells with different degrees of maturation by expression of hepatic fate-conversion factors. METHODS: We have used a combination of lentiviral vectors expressing hepatic fate-conversion factors with Oct4, Sox2, Klf4, and Myc to convert mouse embryonic fibroblasts into hepatic cells. RESULTS: We have generated hepatic cells with progenitor-like features (iHepL cells)...
2016: Stem Cell Research & Therapy
Richard L Gieseck, Thirumalai R Ramalingam, Kevin M Hart, Kevin M Vannella, David A Cantu, Wei-Yu Lu, Sofía Ferreira-González, Stuart J Forbes, Ludovic Vallier, Thomas A Wynn
Fibroproliferative diseases are driven by dysregulated tissue repair responses and are a major cause of morbidity and mortality because they affect nearly every organ system. Type 2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type 2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 overexpression or after infection with Schistosoma mansoni...
July 19, 2016: Immunity
Kazuya Anzai, Hiromi Chikada, Kota Tsuruya, Kinuyo Ida, Tatehiro Kagawa, Yutaka Inagaki, Tesuya Mine, Akihide Kamiya
Liver consists of parenchymal hepatocytes and other cells. Liver progenitor cell (LPC) is the origin of both hepatocytes and cholangiocytic cells. The analyses of mechanism regulating differentiation of LPCs into these functional cells are important for liver regenerative therapy using progenitor cells. LPCs in adult livers were found to form cysts with cholangiocytic characteristics in 3D culture. In contrast, foetal LPCs cannot form these cholangiocytic cysts in the same culture. Thus, the transition of foetal LPCs into cholangiocytic progenitor cells might occur during liver development...
2016: Scientific Reports
Ramadhan B Matondo, Mathilda Jm Toussaint, Klaas M Govaert, Luciel D van Vuuren, Sathidpak Nantasanti, Maarten W Nijkamp, Shusil K Pandit, Peter Cj Tooten, Mirjam H Koster, Kaylee Holleman, Arend Schot, Guoqiang Gu, Bart Spee, Tania Roskams, Inne Borel Rinkes, Baukje Schotanus, Onno Kranenburg, Alain de Bruin
The long term prognosis of liver cancer patients remains unsatisfactory because of cancer recurrence after surgical interventions, particularly in patients with viral infections. Since hepatitis B and C viral proteins lead to inactivation of the tumor suppressors p53 and Retinoblastoma (Rb), we hypothesize that surgery in the context of p53/Rb inactivation initiate de novo tumorigenesis. We, therefore, generated transgenic mice with hepatocyte and cholangiocyte/liver progenitor cell (LPC)-specific deletion of p53 and Rb, by interbreeding conditional p53/Rb knockout mice with either Albumin-cre or Cytokeratin-19-cre transgenic mice...
June 13, 2016: Oncotarget
Leonard J Nelson, Katie Morgan, Philipp Treskes, Kay Samuel, Catherine J Henderson, Claire LeBled, Natalie Homer, M Helen Grant, Peter C Hayes, John N Plevris
Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary human hepatocytes (PHHs). Limited availability, inter-donor functional variability and early phenotypic alterations of PHHs restrict their use; whilst standard cell lines such as HepG2 lack a substantial and variable set of liver-specific functions such as CYP450 activity. Alternatives include the HepG2-derivative C3A cells selected as a more differentiated and metabolically active hepatic phenotype...
June 10, 2016: Basic & Clinical Pharmacology & Toxicology
Ersilia M DeFilippis, Mamta Mehta, Emmy Ludwig
Chronic infection with hepatitis B virus (HBV) has never been described as a risk factor for small bowel adenocarcinoma, although infection is a known risk factor for hepatocellular carcinoma. From May 2009 to December 2014, we implemented an institution-wide screening program for hepatitis B viral serologies prior to starting chemotherapy. Evidence of exposure [hepatitis B core antibody (anti-HBc) positivity in the absence of hepatitis B surface antigen (HBsAg) positivity] was highest in patients with hepatocellular carcinoma (21...
June 2016: Journal of Gastrointestinal Oncology
Aloysious D Aravinthan, Graeme J M Alexander
Cellular senescence is a fundamental, complex mechanism with an important protective role present from embryogenesis to late life across all species. It limits the proliferative potential of damaged cells thus protecting against malignant change, but at the expense of substantial alterations to the microenvironment and tissue homeostasis, driving inflammation, fibrosis and paradoxically, malignant disease if the process is sustained. Cellular senescence has attracted considerable recent interest with recognition of pathways linking aging, malignancy and insulin resistance and the current focus on therapeutic interventions to extend health-span...
October 2016: Journal of Hepatology
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