Journal: Cellular and Molecular Gastroenterology and Hepatology

Abbreviation

Cell Mol Gastroenterol Hepatol

Publisher

Elsevier

Journal Volumes

ISSN

2352-345X

Description

Filters

2020 - 20254
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Publications 1 - 4 of 4
  • Wildtype APC influences the severity of familial adenomatous polyposis
    Item type: Other Journal Item
    Flisikowski, Krzysztof; Perleberg, Carolin; Niu, Guanglin; et al. (2022)
    Cellular and Molecular Gastroenterology and Hepatology
  • Cellular Crosstalk Promotes Hepatic Progenitor Cell Proliferation and Stellate Cell Activation in 3D Co-culture
    Item type: Journal Article
    Haaker, Maya W.; Chang, Jung-Chin; Chung, Brian K.; et al. (2025)
    Cellular and Molecular Gastroenterology and Hepatology
    Background & Aims Following liver damage, ductular reaction often coincides with liver fibrosis. Proliferation of hepatic progenitor cells is observed in ductular reaction, whereas activated hepatic stellate cells (HSCs) are the main drivers of liver fibrosis. These observations may suggest a functional interaction between these 2 cell types. Here, we report on an in vitro co-culture system to examine these interactions and validate their co-expression in human liver explants. Methods In a 3D organoid co-culture system, we combined freshly isolated quiescent mouse HSCs and fluorescently labeled progenitor cells (undifferentiated intrahepatic cholangiocyte organoids), permitting real-time observation of cell morphology and behavior. After 7 days, cells were sorted based on the fluorescent label and analyzed for changes in gene expression. Results In the 3D co-culture system, the proliferation of progenitor cells is enhanced, and HSCs are activated, recapitulating the cellular events observed in the patient liver. Both effects in 3D co-culture require close contact between the 2 different cell types. HSC activation during 3D co-culture differs from quiescent (3D mono-cultured) HSCs and activated HSCs on plastic (2D mono-culture). Upregulation of a cluster of genes containing Aldh1a2, Cthrc1, and several genes related to frizzled binding/Wnt signaling were exclusively observed in 3D co-cultured HSCs. The localized co-expression of specific genes was confirmed by spatial transcriptomics in human liver explants. Conclusion An in vitro 3D co-culture system provides evidence for direct interactions between HSCs and progenitor cells, which are sufficient to drive responses that are similar to those seen during ductular reaction and fibrosis. This model paves the way for further research into the cellular basis of liver pathology.
  • Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology
    Item type: Journal Article
    Sontheimer-Phelps, Alexandra; Chou, David B.; Tovaglieri, Alessio; et al. (2020)
    Cellular and Molecular Gastroenterology and Hepatology
  • An Nrf2-NF-κB Crosstalk Controls Hepatocyte Proliferation in the Normal and Injured Liver
    Item type: Journal Article
    Kuklin, Andrii; Slabber, Coenraad F.; Tortola, Luigi; et al. (2025)
    Cellular and Molecular Gastroenterology and Hepatology
    Background & Aims: The liver has remarkable regenerative and detoxification capacities, which require the Nrf2 and NF-κB transcription factors. Although their individual functions in hepatocytes are well characterized, knowledge about their crosstalk in the adult liver is limited. Methods: We performed AAV8-Cre inducible, hepatocyte-specific knockout of Nrf2, the NF-κB subunit p65, or both genes to determine the individual and combined roles of these transcription factors in the intact liver of male adult mice and after acute CCl4 injury. Mice were characterized using histologic and immunohistochemical stainings, serum and liver bile acid analysis, flow cytometry, and RNA sequencing. To distinguish between cell-autonomous and non-cell-autonomous mechanisms, we generated and analyzed knockout and knockdown AML12 liver cells. Clodronate liposome-mediated macrophage depletion was used to determine the role of these immune cells in hepatocyte proliferation after CCl4 injection. Results: Loss of p65 alone or p65 in combination with Nrf2 caused spontaneous liver inflammation and necrosis. Gene expression profiling identified individual and common target genes of both transcription factors, including genes involved in the control of cell proliferation. Consistent with the expression of these genes, hepatocyte proliferation was reduced by Nrf2 deficiency under homeostatic conditions and after CCl4 injury, which was rescued by additional loss of p65. The increased hepatocyte proliferation in the double-knockout mice was non-cell-autonomous and correlated with macrophage accumulation in the liver. Depletion of macrophages in these mice suppressed hepatocyte proliferation after CCl4 treatment. Conclusions: These results reveal a crosstalk between Nrf2 and p65 in the control of hepatocyte proliferation and point to a key role of macrophages in this effect.
Publications 1 - 4 of 4