Hepatocytes reprogram liver macrophages involving control of TGF-β activation, influencing liver regeneration and injury
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PROVIDER: PRJNA831837 | ENA |
REPOSITORIES: ENA
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Project description:BackgroundMacrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in terms of their activation state and which other liver cell populations may play a role in regulating the same.MethodsReverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy.ResultsWe show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)-dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow-derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell-specific deletion of the TGF-β type II receptor, suggest that the availability of activated TGF-β and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-βRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration.ConclusionsThe availability of activated TGF-β determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-β may represent an important regulatory mechanism in the early phase of liver regeneration in this context.
| S-EPMC10368377 | biostudies-literature
Project description:We aimed at elucidating the molecular and cellular crosstalk how inflammation controls proper liver regeneration. Therefore populations of liver macrophages were studied in genetically different mouse models after PHx using flow cytometry and single cell sequencing. Intercellular communication was examined in vitro, combining proteomics and transcriptomics. We observed marked changes in the composition of macrophage populations in the liver during the regeneration process. A F4/80+/CD11bhigh/CD14high macrophage population that is recruited in a CCR2 dependent manner increased rapidly after PHx. The polarization of the recruited macrophages differs from that under homeostatic conditions , but reappears during the late phase of the process. Proteomics, secretomics, and transcriptomics show that hepatocyte derived signals reduce the availability of active TGFb and thereby affect macrophage polarization and function towards the aforementioned phenotype. Depleting the TGFb type II receptor in myeloid cells phenocopies the hepatocyte-mediated macrophage polarization in vitro and in vivo. Moreover, disrupting TGFb signal transduction in macrophages is associated with increased expression of regeneration-relevant cytokines such as IL-6, reduced resection-induced liver damage and prolongated proliferation phase of hepatocytes in mice. Conclusion: Upon liver injury, hepatocytes have a major influence on the activation state of recruited liver macrophages by regulating the availability of active TGFb and TGFb induces a macrophage phenotype that aggravates injury. Ultimately, this mechanism influences the extent of intervention-induced liver injury as well as the proliferation phase during liver regeneration. In this data set, we investigated the influence of hepatocytes on co-cultured macrophages and vice versa.
2023-07-06 | GSE201467 | GEO
Project description:Background & Aims: Liver fibrosis, a serious medical condition with limited therapies, frequently progresses to cirrhosis and other severe complications. Here, we report that cell cycle-related and expression elevated protein in tumor (CREPT) is up-regulated in liver fibrosis. CREPT preferentially enhances transforming growth factor-β (TGF-β)-activated Smad2/3, rather than the canonical Smad2/3-Smad4 complex, thereby facilitating liver fibrosis progression. Methods: We analyzed public transcriptomic and proteomic datasets from patients with liver fibrosis. Human tissue arrays and mouse models of fibrosis were used to investigate CREPT expression patterns. Hepatocyte-specific overexpression (TG-CREPT) and deletion (CREPThep-/-) mice were subjected to acute liver injury (24 h, high-dose CCl4), chronic fibrosis (28 d, low-dose CCl4), and bile duct ligation (BDL) to induce liver fibrosis. Histological, biochemical, and RNA-sequencing (RNA-seq) analyses and CUT&Tag experiments were conducted. Results: CREPT is predominantly enriched in hepatocytes and upregulated in fibrotic liver tissues from patients and mice induced by CCl4 or BDL. Overexpression of CREPT in hepatocytes exacerbates liver injury and fibrosis in mice under acute or chronic CCl4 exposure and BDL challenge. In contrast, hepatocyte-specific deletion of CREPT significantly alleviates liver fibrosis. Mechanistically, CREPT aggravates TGF-β/Smad signaling pathway, preferentially interacting with Smad2/3, but not Smad4, to promote inflammatory responses, and up-regulates fibrogenic genes, including Cebpd, Fosl2 and Fn1. Intriguingly, targeting CREPT with LNP-delivered siRNA (LNP-siCREPT) and GalNAc-delivered siRNA (GalNAc-siCREPT) significantly reduces pre-existing liver fibrosis in mice. Conclusions: Our findings identify a promoting effect of CREPT on liver fibrosis through TGF-β-activated Smad2/3 but not Smad4. Targeting CREPT represents a potential therapeutic strategy for liver fibrosis.
2025-08-28 | GSE306355 | GEO
Project description:Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity
| PRJNA528430 | ENA
Project description:Thiele2013 - Liver hepatocytes
The model of liver hepatocytes metabolism is derived from the community-driven global reconstruction of human metabolism (version 2.02, MODEL1109130000
).
This model is described in the article:
A community-driven global reconstruction of human metabolism.
Thiele I, et al
.
Nature Biotechnology
Abstract:
Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven,
consensus 'metabolic reconstruction', which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared
with its predecessors, the reconstruction has improved topological and functional features, including ~2x more reactions and ~1.7x more unique metabolites. Using
Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic
data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically
generated a compendium of 65 cell type-specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will
facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/.
This model is hosted on BioModels Database
and identified by: MODEL1310110014
.
To cite BioModels Database, please use: BioModels Database: An enhanced,
curated and annotated resource for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer
to CC0 Public Domain Dedication
for more information.
2005-01-01 | MODEL1310110014 | BioModels
Project description:Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic-tissues are largely unknown. Here, we show that in the liver, the classical steroidogenic enzyme, Cyp17a1, forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyses the production of a hormone-ligand (DHEA) for PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signalling, involving the receptors FXR, SHP and LRH-1. Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.
2020-01-16 | PXD012876 | Pride
Project description:Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity (RNA-Seq)
| PRJNA528435 | ENA
Project description:Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity (ATAC-Seq)
| PRJNA528436 | ENA
Project description:Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity (ChIP-Seq)
| PRJNA528437 | ENA