Impact of inducing hypercholesterolemia on Kupffer cells
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Mus musculus
SUBMITTER: Dussaud sebastien
PROVIDER: E-MTAB-12611 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Kupffer cells (KCs) are the tissue resident macrophage population of the liver. With this experiment, we sought to investigate the potential consequences of decreasing embryonically-derived KC numbers on liver gene expression in the context of hypercholesterolemia. 3-month-old CD207-DTR x LDL-receptor deficient (C57BL6J background) female mice were injected with diphtheria toxin (DT) or heat-inactivated DT. Mice were then fed a cholesterol-rich diet to induce hypercholesterolemia. RNA sequencing was performed on liver RNA samples after 4 weeks of diet.
2024-09-05 | E-MTAB-12744 | biostudies-arrayexpress
Project description:Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is initially responding site, or if atherogenic-dyslipidemia affects other organs simultaneously, is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB-lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA-seq revealed an Kupffer cell-specific transcriptional program that was not activated by a high-fat diet alone, or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.
2024-02-05 | GSE254879 | GEO
Project description:Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is initially responding site, or if atherogenic-dyslipidemia affects other organs simultaneously, is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB-lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA-seq revealed an Kupffer cell-specific transcriptional program that was not activated by a high-fat diet alone, or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.
2024-02-05 | GSE254971 | GEO
Project description:Impact of inducing hypercholesterolemia on Kupffer cells
| PRJEB59614 | ENA
Project description:Kupffer cells (KCs) self-renew by local proliferation in the adult independently from monocytes (Mos). However, how they maintain during chronic metabolic disorders such as non-alcoholic steatohepatitis (NASH) remains ill-defined. We characterized KCs during NASH and observed diversity in the KC pool, with a significant fraction of monocyte-derived KCs (MoKCs). Here, we aim to uncover the transcriptional landscapes of KCs subsets found in a mouse model of methionine and choline deficient (MCD)-diet induced non-alcoholic steatohepatitis (NASH).
2020-12-04 | GSE138778 | GEO
Project description:There is an evident, unmet need to develop a commercially available in vitro system that can model inflammatory states of the liver and predict immune-mediated hepatotoxicity of drugs and xenobiotics taken under inflamed conditions. Hepatocyte-Kupffer cell co-cultures can model inflammation-mediated hepatotoxicity; however, Kupffer cell (KC) source remains an important bottleneck for the development of such models. Primary human Kupffer cells (PHKCs) are costly, limited in availability and exhibit donor variability. An alternative cell source for KCs has not been reported. Important paradigm shift from the classical dogma of adult blood-circulating monocyte-derived macrophages to intrahepatic precursor/fetal monocyte-derived macrophages has shed new light into the origin of KCs in vivo. Based on these recent findings, we report here, a novel method to generate human KCs in vitro from stem cells (hPSC-KCs) via fetal monocytes. hPSC-KCs expressed macrophage markers, CD11, CD14, CD68, CD163 and CD32 at gene and protein level and exhibited functional properties such as phagocytosis and Interleukin-6 and Tumor Necrosis Factor-4alpha production upon activation. Importantly, molecular signature, liver-macrophage specific CLEC-4F expression and cytokines production levels of hPSC-KCs were similar to PHKCs but different from non-liver macrophages. We used an inflammatory liver co-culture model to demonstrate that activated hPSC-KCs, but not non-liver macrophages, were able to recapitulate effects of PHKCs when stimulated with paradigm hepatotoxicants. hPSC-KCs developed in this study offer a renewable human cell source for liver-specific macrophages which can be used to develop in vitro systems for modelling the inflammatory state of the liver. Gene expression profiles of 9 samples were determined using Human Gene 2.0 ST Array. These 9 samples included three replicates each of PHKCs (primary human Kupffer cells), human pluripotent stem cell-dervied Kupffer cells (hPSC-KCs) and non-liver macrophages (NL-Mφ).
2019-01-07 | GSE99734 | GEO
Project description:Kupffer cells (KCs) are tissue-resident macrophages which colonize the developing liver early during embryogenesis1. Throughout development and adulthood, KCs have distinct core functions that are essential for liver and organismal homeostasis, such as supporting fetal erythropoiesis as well as postnatal erythrocyte recycling and liver metabolism2. KCs acquire their tissue-specific transcriptional signature immediately after colonizing the liver, mature together with the tissue, and adapt to the tissue’s function1,3,4. However, whether perturbation of macrophage core functions during development may contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a maternal obesity model to disturb KC functions during gestation. We show that offspring born to obese mothers develop fatty liver disease that is accompanied by a local pro-inflammatory response, a phenotype that is augmented if the offspring is kept on control diet after birth. Further, transcriptional analyses reveal that KCs undergo developmental programming through the maternal high-fat diet, which lasts until adulthood. The offspring’s KC developmental programming is irreversible despite the switch to control diet and leads to increased lipid uptake in hepatocytes mediated via paracrine factors stemming from KCs. The transcriptional programming of KCs and the fatty liver disease phenotype are rescued by genetic depletion of hypoxia-inducible factor alpha (Hif1a) in macrophages during gestation. These results demonstrate that macrophages rely on an undisturbed development to fulfil their core functions and support organ homeostasis during adulthood, and establish developmental programming of KCs as a therapeutic strategy for metabolic disorders, such as fatty liver disease.
2023-08-22 | GSE237405 | GEO
Project description:Kupffer cells (KCs) are tissue-resident macrophages which colonize the developing liver early during embryogenesis1. Throughout development and adulthood, KCs have distinct core functions that are essential for liver and organismal homeostasis, such as supporting fetal erythropoiesis as well as postnatal erythrocyte recycling and liver metabolism2. KCs acquire their tissue-specific transcriptional signature immediately after colonizing the liver, mature together with the tissue, and adapt to the tissue’s function1,3,4. However, whether perturbation of macrophage core functions during development may contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a maternal obesity model to disturb KC functions during gestation. We show that offspring born to obese mothers develop fatty liver disease that is accompanied by a local pro-inflammatory response, a phenotype that is augmented if the offspring is kept on control diet after birth. Further, transcriptional analyses reveal that KCs undergo developmental programming through the maternal high-fat diet, which lasts until adulthood. The offspring’s KC developmental programming is irreversible despite the switch to control diet and leads to increased lipid uptake in hepatocytes mediated via paracrine factors stemming from KCs. The transcriptional programming of KCs and the fatty liver disease phenotype are rescued by genetic depletion of hypoxia-inducible factor alpha (Hif1a) in macrophages during gestation. These results demonstrate that macrophages rely on an undisturbed development to fulfil their core functions and support organ homeostasis during adulthood, and establish developmental programming of KCs as a therapeutic strategy for metabolic disorders, such as fatty liver disease.
2023-08-22 | GSE237393 | GEO
Project description:Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages long known for their scavenger and phagocytic functions. KCs are also able to present antigen to CD8+ T cells and promote either T cell tolerance or full effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection – where HBV-specific naïve CD8+ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction – to identify a subset of KCs (referred to as KC2) that improves the antiviral function of T cells upon exogenous administration of IL-2. Mechanistically, KC2 were found to be both enriched in the IL-2 sensing machinery and poised to productively cross-present hepatocellular antigens in response to this cytokine. Removing MHC-I from all KCs – including KC2 – as well as selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. Together, these findings indicate that, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment and suggest new strategies for boosting T cell immunity in the liver.
2021-09-01 | GSE152211 | GEO
Project description:Aim: To find out the effects of small extracellular vesicles (sEVs) from short-term activated and long-term activated hepatic stellate cells (HSCs) on Kupffer cells (KCs) and bone marrow-derived monocytes (MOs). Methods: For the isolation of HSC-derived sEVs, culture media (CMs) from Day 0 to Day 3 and Day 7 to Day 14 were collected. The sEVs from Day 0 to Day 3 HSC CMs were referred to as short-term activated HSC-sEVs (3dHSC-sEVs), and those from Day 7 to Day 14 HSC CMs were referred to as long-term activated HSC-sEVs (14dHSC-sEVs). Purified primary rat KCs and MOs were cocultured with 3dHSC- or 14dHSC-sEVs for 48 h. HSC-sEVs cocultured KCs or MOs were lysed in TRIzol (Life Technologies) for RNA sample preparation at the indicated time points.
2024-08-29 | E-MTAB-12754 | biostudies-arrayexpress