Nina Graffmann

Projects: LiSyM-Krebs Partnering

Institutions: Universitätsklinikum Düsseldorf - Institut für Stammzellforschung und Regenerative Medizin

https://orcid.org/0000-0002-1229-0792
Nachiket Vartak palproject_administratorasset_housekeeper

Projects: Molecular Steatosis - Imaging & Modeling (LiSyM-MSIM), LiSyM network, LiSyM-Krebs Partnering

Institutions: Leibniz-Institut für Arbeitsforschung (IfADo)

https://orcid.org/0000-0001-8813-4799
Johannes Bode

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM-Krebs Partnering, Forschungsnetzwerk LiSyM-Krebs, C-TIP-HCC network

Institutions: Universitätsklinikum Düsseldorf - Klinik für Gastroenterologie, Hepatologie und Infektiologie

Christian Ehlting

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network

Institutions: Universitätsklinikum Düsseldorf - Klinik für Gastroenterologie, Hepatologie und Infektiologie

https://orcid.org/0000-0003-0103-1856
Hepatocellular Carcinoma

The model studies the influence of hepatocyte–sinusoid alignment (HSA), i.e. the orientation of the division plane such that daughter hepatocytes align with nearby sinusoids, on the shape of tumor nodules in liver lobules. It employs the structure of the model ‘Liver Regeneration from CCl4’ (https://seek.lisym.org/models/19).

Originally, Höhme et al. (https://doi.org/10.1007/s11538-017-0375-1) employed a center-based model. Here, the model is encoded in the standardized language MorpheusML. ...

Creators: Diego Jahn, Michael Kücken, Lutz Brusch

Submitter: Diego Jahn

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Liver Regeneration from CCl4

In the experimental paradigm of CCl4 intoxication of mice, hepatocytes around the central vein (located in the center of an idealized hexagonal liver lobule) are dying and are subsequently replaced by new hepatocytes, largely through activation of proliferation in the remaining hepatocytes.

Alignment of daughter hepatocytes along the orientation of the closest sinusoid, a process which is named hepatocyte-sinusoid alignment (HSA), was proposed by Höhme et al. (https://doi.org/10.1073/pnas.0909374107) ...

Creators: Diego Jahn, Michael Kücken, Lutz Brusch

Submitter: Diego Jahn

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SOP : Western diat mouse housing and feeding

SOP Western diat mouse housing and feeding

Creator: Ina Biermayer

Submitter: Olga Krebs

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Insulin Determines Transforming Growth Factor β Effects on Hepatocyte Nuclear Factor 4α Transcription in Hepatocytes

Abstract (Expand)

Loss of hepatocyte nuclear factor 4α (HNF4α) expression is frequently observed in end-stage liver disease and associated with loss of vital liver functions, thus increasjng mortality. Loss of HNF4α … expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-β. However, details of how HNF4α is suppressed are largely unknown to date. This study reports that TGF-β does not directly inhibit HNF4α but contributes to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CREB-binding protein/p300 to the HNF4α promoter. The recruitment of CREB-binding protein/p300 is indispensable for CCAAT/enhancer-binding protein α (C/EBPα) binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitro observation, 67 of 98 patients with hepatic HNF4α express both phospho-SMAD2 and C/EBPα, whereas 22 patients without HNF4α expression lack either phospho-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibits C/EBPα transcription. Therefore, long-term TGF-β incubation results in C/EBPα depletion, which abrogates HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter is abolished by insulin. Two-thirds of patients without C/EBPα lack membrane glucose transporter type 2 expression in hepatocytes, indicating insulin resistance. Taken together, hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation.

Authors: Rilu Feng, Chenhao Tong, Tao Lin, Hui Liu, Chen Shao, Yujia Li, Carsten Sticht, Kejia Kan, Xiaofeng Li, Rui Liu, Sai Wang, Shanshan Wang, Stefan Munker, Hanno Niess, Christoph Meyer, Roman Liebe, Matthias P. Ebert, Steven Dooley, Hua Wang, Huiguo Ding, Hong-Lei Weng

Date Published: 1st Oct 2023

Publication Type: Journal

Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease.

Abstract (Expand)

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic … development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

Authors: C. Mayer, S. Nehring, M. Kucken, U. Repnik, S. Seifert, A. Sljukic, J. Delpierre, H. Morales-Navarrete, S. Hinz, M. Brosch, B. Chung, T. Karlsen, M. Huch, Y. Kalaidzidis, L. Brusch, J. Hampe, C. Schafmayer, M. Zerial

Date Published: 31st Jul 2023

Publication Type: Journal

Diploid hepatocytes drive physiological liver renewal in adult humans

Abstract (Expand)

Physiological liver cell replacement is central to maintaining the organ’s high metabolic activity, although its characteristics are difficult to study in humans. Using retrospective radiocarbon (14C) … birth dating of cells, we report that human hepatocytes show continuous and lifelong turnover, allowing the liver to remain a young organ (average age <3 years). Hepatocyte renewal is highly dependent on the ploidy level. Diploid hepatocytes show more than 7-fold higher annual birth rates than polyploid hepatocytes. These observations support the view that physiological liver cell renewal in humans is mainly dependent on diploid hepatocytes, whereas polyploid cells are compromised in their ability to divide. Moreover, cellular transitions between diploid and polyploid hepatocytes are limited under homeostatic conditions. With these findings, we present an integrated model of homeostatic liver cell generation in humans that provides fundamental insights into liver cell turnover dynamics.

Authors: Paula Heinke, Fabian Rost, Julian Rode, Palina Trus, Irina Simonova, Enikő Lázár, Joshua Feddema, Thilo Welsch, Kanar Alkass, Mehran Salehpour, Andrea Zimmermann, Daniel Seehofer, Göran Possnert, Georg Damm, Henrik Druid, Lutz Brusch, Olaf Bergmann

Date Published: 1st Jun 2022

Publication Type: Journal

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