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Hepatocytes induces properties of wound healing type and regulatory macrophages in co-cultivated BMDM

ABSTRACT: The liver comprises the body´s largest pool of macrophages constituting approximately 80 % of all sessile tissue macrophages of the body. After liver damage monocyte-derived macrophages are recruited into the liver and were here affected by a micro milieu which is considerably influenced by hepatocytes. Up to now the complex network that determines the differentiation and function of liver macrophages and the impact of the intercellular communication between macrophages and the other parenchymal and non-parenchymal cell types of the liver is not well understood. The present study investigates the role of the intercellular communication between macrophages and hepatocytes on macrophage differentiation and function. Under physiological conditions the sinusoidal endothelial cell layer and the space of Dissé separate macrophages and hepatocytes from each other. Therefore the study focuses on the impact of the intercellular communication via soluble mediators on the differentiation of bone marrow derived macrophages (BMDM), which were recruited to the liver after liver injury, in co-culture models with highly purified primary murine hepatocytes embedded in a sandwich collagen matrix.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver, Macrophage

SUBMITTER: Gereon Poschmann

LAB HEAD: Gereon Poschmann

PROVIDER: PXD012136 | Pride | 2023-07-07

REPOSITORIES: Pride

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Hepatocytes reprogram liver macrophages involving control of TGF-β activation, influencing liver regeneration and injury

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

The Hepatocyte Proteome in Organotypic Rat Liver Models and the Influence of the Local Microenvironment

Project description:Liver models that closely mimic the in vivo microenvironment are central for understanding liver functions, capabilities, and intercellular communication processes. Whereas hepatocyte monolayers de-differentiate after only a few days in culture, constructs consisting of hepatocytes and non-parenchymal cells (NPC) separated by a polyelectrolyte multilayer (PEM) provide maintenance of hepatic phenotypes. To better understand the mechanisms and processes that underlie organotypic liver model function, hepatocyte protein abundances in the presence and absence of liver sinusoidal endothelial cells (LSECs) were compared to hepatocyte monolayers. The presence of the PEM led to increases in proteins associated with hepatocyte lipid metabolism, with mitochondrial-based β-oxidation and peroxisomal proteins found in higher abundance. It was also demonstrated that the presence of LSECs modulates levels of carboxylesterases and other phase I and phase II enzymes. These results are discussed in relation to intercellular signaling and hepatocyte function.

2017-07-06 | PXD002491 | Pride

Single-cell Transcriptomic Architecture Reveals Dynamic Heterogeneity and Intracellular Crosstalk Features Which Triggers Liver Mallory-Denk Bodies Pathogenesis

Project description:Liver cell injury causes balloon hepatocytes and Mallory-Denk Bodies (MDBs) formation impeding liver parenchymal regeneration. MDBs are an intracellular deposition of misfolded protein and typical features of distinct chronic liver disease. Therefore, a comprehensive understanding of cellular heterogeneity and intercellular signaling of MDBs formation is essential to elucidate the mechanisms driving MDBs formation and chronic liver disease progression and to develop therapeutic approaches.

2023-06-21 | GSE201569 | GEO

Human liver cells proteome

Project description:The human liver functions through a complex interplay of parenchymal and non-parenchymal cells, which participate in performing many essential aspects of metabolism and secretion. Mass spectrometry-based proteomic analysis of intact tissue has improved the understanding of these processes, by providing an in-depth view of the human liver proteome. However, the predominance of parenchymal cells, i.e. hepatocytes, means that the total tissue proteome mainly reflects hepatocyte expression. In this study, we therefore used quantitative label-free proteomic analysis to analyze the proteomes of the major parenchymal and non-parenchymal cell types in the human liver, i.e. hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells. We found that our data recapitulated specific functional differences between cell types, meaning that it can be used to reliably probe various aspects of cellular interplay. Thus, the data we provide constitutes a unique resource for exploring the human liver proteome at major cell type resolution.

2020-04-09 | PXD012615 | Pride

High Glucose Macrophage Exosomes Enhance Atherosclerosis by Driving Cellular Proliferation & Hematopoiesis [RNA-Seq]

Project description:Hyperglycemia is a recognized risk factor for cardiovascular complications in diabetes. While hyperglycemia is known to cause microRNA dysregulation that contributes to cellular activation, whether it can do so through intercellular communication via extracellular vesicles (EVs) is not known. We investigated whether EVs produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe−/−mice with exosomes produced by bone marrow‐derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control. Repeated infusion of BMDM–HG-exo led to a robust increase in hematopoiesis leading to augmented circulating myeloid cell numbers. Four weeks of BMDM–HG-exo infusions increased atherosclerotic lesion sizes with an accumulation of macrophage and apoptotic cells in the aortic root. Transcriptome-wide analysis of naïve cultured macrophages treated with BMDM–HG-exo showed an upregulation of genes associated with cell proliferation. Furthermore, BMDM–HG-exo reprogramed energy metabolism in recipient macrophages with an upregulation of glycolytic activity. Plasma EVs isolated from human subjects with type II diabetes exerted similar cell signaling when incubated with cultured human macrophages. Lastly, profiling microRNA in BMDM–HG-exo and human diabetic plasma EVs converged on miR-486 as commonly enriched. In conclusion, our findings show that EVs serve to communicate detrimental

2021-08-18 | GSE162961 | GEO

High Glucose Macrophage Exosomes Enhance Atherosclerosis by Driving Cellular Proliferation & Hematopoiesis [miRNA-Seq]

2021-08-18 | GSE162958 | GEO

Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney

Project description:Background & Aims: Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers due to its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through the complex intercellular signaling. However, the liver organogenetic mechanism, especially the role of adult hepatocytes at ectopic sites, remains unknown. In this study, we demonstrate that hepatocytes alone spurred liver organogenesis to form an organ-sized complex 3D liver that exhibited native liver architecture and functions in the kidneys of mice. Methods: Isolated hepatocytes were transplanted under the kidney capsule of monocrotaline (MCT) and partial hepatectomy (PHx)-treated mice. To determine the origin of NPCs in neo-livers, hepatocytes were transplanted into MCT/PHx-treated green fluorescent protein (GFP) transgenic mice or wild-type mice transplanted with bone marrow (BM) cells isolated from GFP mice. Results: Hepatocytes engrafted at the subrenal space of mice underwent continuous growth in response to a chronic hepatic injury in the native liver. More than 1.5 yrs later, whole organ-sized liver tissues having a greater mass than those of the injured native liver had formed. Most remarkably, we revealed that at least three types of NPCs with similar phenotypic features to the liver NPCs were recruited from the host tissues including BM. The neo-livers in the kidney exhibited liver-specific functions and architectures, including sinusoidal vascular systems, zonal heterogeneity, and emergence of bile duct cells. Furthermore, the neo-livers successfully rescued the mice with lethal liver injury. Conclusion: Our data clearly showed that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment.

2017-12-25 | GSE99141 | GEO

Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver

Project description:The adult liver has exceptional ability to regenerate, but how it sustains normal metabolic activities during regeneration remains unclear. Here, we use partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ~22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results reveal that following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Importantly, through combined analysis of gene regulatory networks and cell- cell interaction maps, we find that regenerating hepatocytes redeploy key developmental gene regulons, which are guided by extensive ligand–receptor mediated signaling events between hepatocytes and non-parenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferation requirements of a regenerating liver.

2021-02-01 | GSE151309 | GEO

A healthy human liver cell atlas reveals hepatic stellate cell heterogeneity

Project description:We generated a high-resolution cellular atlas of the healthy human liver by profiling the transcriptome of more than 25,000 individual liver cells using droplet-based RNA-sequencing. Recently published datasets and in situ hybridization were integrated to confirm, validate and locate newly identified cell populations. We identified, annotated and characterized a total of 23 cell subpopulations that represent the degree of heterogeneity of parenchymal (i.e. hepatocytes and cholangiocytes) and non-parenchymal liver cells (i.e. endothelial cells, stellate cells, macrophages and lymphoid cells). We successfully classified human hepatocytes and liver sinusoidal endothelial cells along the porto-central axis and for the first time reveal the existence of functionally specialized pericentral GPC3+ and periportal HHIP+ DBH+ hepatic stellate cells in the healthy human liver. Our study provides a description of the different cell compartments that enter into the composition of a healthy human liver and currently constitutes the biggest single-cell RNA sequencing dataset available on human healthy hepatocytes and hepatic stellate cells. We identified subsets of hepatic stellate cells characterized by distinct localization and physiological functions.

2021-04-26 | GSE158723 | GEO

Hepatocyte SREBP signaling mediates clock communication within the liver [ATAC-seq]

Project description:Rhythmic intraorgan communication coordinates environmental signals and cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific knockout of core components of the molecular clock, Rev-erba and b (ReverbhDKO), alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in non-parenchymal cells (NPC) of the liver. Here we report that in diet induced obesity (DIO)-caused fatty liver, hepatocyte SREBP cleavage-activating protein (SCAP) is required for ReverbhDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in Kupffer cells (KC). Integrative analyses of isolated hepatocytes and Kupffer cells uncovered potential signals, including secreted polypeptides and metabolites, that gain rhythmicity in the absence of REV-ERBs in a SCAP-dependent manner. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in DIO and fatty liver disease.

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