Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function
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PROVIDER: PRJNA670425 | ENA |
REPOSITORIES: ENA
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Project description:Jak3 is the only non-promiscuous member of the Jak family of secondary messengers. Jak3–/– mice display defective T and NK cell development, which results in a SCID phenotype. As a result, studies to date have focused on understanding and targeting the cell-autonomous role of Jak3 in immunity, while functional Jak3 expression outside the hematopoietic system remains largely unreported. We show that Jak3 is expressed in endothelial cells across hematopoietic and non-hematopoietic organs, with heightened expression in the bone marrow. The bone marrow niche is understood as a network of different cell types that regulate hematopoietic function. We show that the Jak3–/– bone marrow niche is deleterious for the maintenance of long-term repopulating hematopoietic stem cells (LT-HSCs) and that JAK3-overexpressing endothelial cells have increased potential to expand LT-HSCs in vitro. Increased arterial zonation in the bone marrow of Jak3–/– mice further situates Jak3 as a marker of sinusoidal endothelium. This work may serve to identify a novel function for a highly specific tyrosine kinase in the bone marrow vascular niche and to further characterize the LT-HSC function of sinusoidal endothelium.
2021-10-20 | GSE159755 | GEO
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Project description:Endothelial cells were transduced with different genes modulating signaling pathways and compared to GFP transduced control group to identify changes in the expression of the angiocrine factors. The experiment compared endothelial genetic changes upon Akt, MAP kinase and PymT activation.
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Project description:We studied metabolic angiocrine mechanisms by which endothelial cell_ECs_ can contribute to muscle regeneration from ischemia by using endothelial specific pfkfb3 knockout mice_pfkfb3DEC_ after hind-limb ischemia_HLI_. During muscle regeneration, monocytes are recruited to the injured area and rapidly become macrophages which initially exhibit a more pro-inflammatory M1-like phenotype but soon thereafter functionally repolarize towards an M2-like phenotype to actively support muscle regeneration. Interestingly, macrophages derived from pfkfb3DEC failed to polarized to M2-like macrophages after HLI. Reduced macrophage polarization impairs angiogenesis and muscle regeneration. The RNAseq data are pfkfb3DEC and pfkfb3WT muscle derived macrophages 3 days after HLI.
2020-05-18 | GSE148584 | GEO
Project description:Endothelial cells were transduced with different genes modulating signaling pathways and compared to GFP transduced control group to identify changes in the expression of the angiocrine factors.
2011-12-31 | GSE24093 | GEO
Project description:Dysfunction of the vascular angiocrine system is critically involved in regenerative defects and fibrosis of injured organs. Previous studies have identified various angiocrine factors and found that risk factors such as aging and metabolic disorders can disturb the vascular angiocrine system in fibrotic organs. One existing key gap is what sense the fibrotic risk to modulate the vascular angiocrine system in organ fibrosis. Here, using human and mouse data, we discovered that the metabolic pathway hydrogen sulfide (H2S)-AMP-activated protein kinase (AMPK) is a sensor of fibrotic stress and serves as a key mechanism upregulating the angiocrine factor plasminogen activator inhibitor-1 (PAI-1) in endothelial cells to participate in lung fibrosis.
2024-01-31 | GSE250474 | GEO
Project description:T-ALL is characterized by deregulation of transcriptional control and impairment of epigenetic homeostasis. We observed that T-ALL cases with mutations in the IL7R-JAK-STAT pathway frequently harbor inactivating mutations in the PRC2 complex, in particular SUZ12 mutations. PRC2 is an epigenetic complex responsible for writing the H3K27me3 mark associated with gene repression. To assess whether loss of SUZ12 cooperates with mutant JAK3 signaling during T-ALL development, we expressed the JAK3(M511I) mutant in mouse bone marrow cells in vivo and tested the effect of Cas9-mediated inactivation of Suz12 on leukemia development. The mice developed a T-cell leukemia that infiltrated most hematological organs (bone marrow, thymus, spleen, lymph nodes, blood). At time of sacrifice the majority of cells in the blood and hematopoietic organs was JAK3(M511I) positive and Suz12 negative. Reduced Suz12 protein and H3K27me3 levels were confirmed with flow cytometry. Moreover, JAK3(M511I) also cooperates with Suz12 gRNA-mediated inactivation in vitro. Pro-T cells carrying both JAK3(M511I) and Suz12 gRNA were able to transform to IL7 independent growth, whereas single mutant (JAK3(M511I) only or Suz12 gRNA only) pro-T cells could not. In order to get insight in the mechanism of cooperation between JAK3 mutant signaling and Suz12 inactivation, we performed and integrated RNA- and ChIP-sequencing (Suz12, H3K27me3, H3K27Ac, H3K4me1, H3K4me3) on leukemic cells from the mice. This showed a global upregulation of many genes, including known PRC2 target genes upon loss of Suz12. Moreover, Suz12 was bound to promoters of Wnt signaling genes (Fzd7, Lrp4) and Wnt target genes (Axin2, Jag2, Mmp9), concomitant with high H3K27me3 levels. Loss of Suz12 led to drastic reduction of H3K27me3 at these loci and upregulation of these Wnt genes. As Wnt signaling is ectopically activated, we wanted to test whether JAK3(M511I) + Suz12 gRNA cells are more sensitive to Wnt inhibitor. JAK3(M511I) + Suz12 pro-T cells and leukemic spleen cells exhibited increased sensitivity to Wnt inhibitor compared to JAK3 mutant control cells, indicating that Wnt signaling contributes to the cooperation between Suz12 loss and JAK3 mutant signaling. In conclusion, our data show that Suz12 inactivation cooperates with mutant JAK3 signaling to drive leukemia development in vivo and demonstrates the use of Cas9 transgenic mice to study the role of tumor suppressor genes in T-ALL mouse models. Moreover, Suz12 loss leads to ectopic activation of Wnt signaling, a pathway contributing to the cooperation of Suz12 loss and JAK3 mutant signaling that can also be targeted with inhibitors.
2019-03-01 | GSE122496 | GEO
Project description:Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes
2023-12-28 | PXD033942 | Pride
Project description:Endothelial cells control muscle regeneration through angiocrine lactate
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Project description:Angiocrine signaling by liver sinusoidal endothelial cells (LSEC) regulates liver functions such as liver growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master regulator of LSEC specification during development. Here, we studied endothelial GATA4 in the adult liver and in hepatic disease pathogenesis. We generated adult Clec4g-icretg/0xGata4fl/fl (Gata4LSEC KO) mice with deficiency of Gata4 in LSEC. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in-situ hybridization, and by expression profiling and ATAC-sequencing of isolated LSEC. For liver regeneration, partial hepatectomy was performed. As models of liver fibrosis, CDAA diet and chronic CCl4 exposure were applied. Human single cell RNAseq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers. Genetic Gata4 deficiency in LSEC in adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch including de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated Myc mediated angiocrine PDGFB expression. In CDAA diet-induced perisinusoidal liver fibrosis, LSEC showed repression of GATA4, activation of MYC and the profibrotic angiocrine switch already detected in Gata4LSEC KO mice. Comparison of CDAA-fed Gata4LSEC KO and control mice demonstrated that endothelial Gata4 indeed protects from dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, Gata4-positive LSEC and endothelial Gata4 target genes were reduced, while non-LSEC endothelial cells and Myc target genes including PDGFB were enriched. Endothelial GATA4 protects from perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling on the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRβ axis offer a promising strategy for the prevention and treatment of liver fibrosis.
2020-10-21 | GSE154827 | GEO