Tie2-expressing monocytes/macrophages promote cerebral revascularization in peri-infarct lesions upon ischemic insult.
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ABSTRACT:
SUBMITTER: Sheng Y
PROVIDER: S-EPMC8349906 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A third of patients with critical limb ischemia (CLI) will eventually require limb amputation. Therapeutic neovascularization using unselected mononuclear cells to salvage ischemic limbs has produced modest results. The TIE2-expressing monocytes/macrophages (TEMs) are a myeloid cell subset known to be highly angiogenic in tumours. This study aimed to examine the kinetics of TEMs in patients with CLI and whether these cells promote neovascularization of the ischemic limb. Here we show that there are 10-fold more circulating TEMs in CLI patients, and removal of ischemia reduces their numbers to normal levels. TEM numbers in ischemic muscle are two-fold greater than normoxic muscle from the same patient. TEMs from patients with CLI display greater proangiogenic activity than TIE2-negative monocytes in vitro. Using a mouse model of hindlimb ischemia, lentiviral-based Tie2 knockdown in TEMs impaired recovery from ischemia, whereas delivery of mouse macrophages overexpressing TIE2, or human TEMs isolated from CLI patients, rescued limb ischemia. These data suggest that enhancing TEM recruitment to the ischemic muscle may have the potential to improve limb neovascularization in CLI patients.
| S-EPMC3779448 | biostudies-literature
Project description:Background:Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie2)-expressing monocytes (TEMs) are a highly proangiogenic subset of myeloid cells, which are characterized by expressing the angiopoietin receptor Tie2 with pro-tumor activity. Purpose:The present study aimed to determine the clinical value of circulating TEMs (cTEMs) for cervical cancer. Patients and Methods:Peripheral blood mononuclear cells (PBMCs) were obtained from 7 healthy volunteers, 17 uterine fibroid patients, 24 cervical intraepithelial neoplasia (CIN) II patients, 31 CIN III patients and 99 patients with cervical cancer. The cTEMs were evaluated by the ratio of Tie2+ CD14+ cells to all CD14+ monocytes in the PBMCs through flow cytometry. The diagnostic value of cTEM was assessed by receiver operating characteristic (ROC) curves and the correlation between cTEM and clinicopathological characters in cervical cancer patients was analyzed. Results:The proportion of cTEMs was gradually increasing from healthy volunteers to patients with non-invasive lesions, then to cervical cancer patients. The area under the ROC curve was 0.913 when the level of cTEMs was used to distinguish cervical cancer from all the other women ranging from healthy volunteers to CIN III patients. In cervical cancer, an increased cTEM fraction was significantly correlated with advanced tumor stage, larger tumor size, lymph node metastasis (LNM), deep stromal infiltration, parametrial involvement and lymph-vascular space invasion and was an independent risk factor for LNM. Conclusion:The cTEM proportion might be a promising biomarker for the malignant transformation of cervical lesions and the progression of cervical cancer.
| S-EPMC7490041 | biostudies-literature
Project description:Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph-) myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2) have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs), and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62-CCR2- (TEMs) and their frequency was higher (p = 0.008) in spleen tissue-derived mononuclear cells (MNCs) of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ.
| S-EPMC4900622 | biostudies-literature
Project description:We have conducted the first study to determine the diagnostic potential of the CD14++CD16+ intermediate monocytes as compared to the pro-angiogenic subset of CD14++CD16+TIE2+ TIE2-expressing monocytes (TEMs) in cancer. These monocyte populations were investigated by flow cytometry in healthy volunteers (N?=?32) and in colorectal carcinoma patients with localized (N?=?24) or metastatic (N?=?37) disease. We further determined blood levels of cytokines associated with monocyte regulation. The results revealed the intermediate monocyte subset to be significantly elevated in colorectal cancer patients and to show the highest frequencies in localized disease. Multivariate regression analysis identified intermediate monocytes as a significant independent variable in cancer prediction. With a cut-off value at 0.37% (intermediate monocytes of total leukocytes) the diagnostic sensitivity and specificity ranged at 69% and 81%, respectively. In contrast, TEM levels were elevated in localized cancer but did not differ significantly between groups and none of the cytokines correlated with monocyte subpopulations. Of interest, in vitro analyses supported the observation that intermediate monocytes were more potently induced by primary as opposed to metastatic cancer cells which may relate to the immunosuppressive milieu established in the advanced stage of metastatic disease. In conclusion, intermediate monocytes as compared to TIE2-expressing monocytes are a more sensitive diagnostic indicator of colorectal cancer.
| S-EPMC3433422 | biostudies-literature
Project description:To identify the gene expressing profiles of TIE2 expressing Monocytes(TEMs), we have employed the Agilent lncRNA Gene Expression 4×180K(Design ID:042818) microarray. Human peripheral blood mononuclear cells (PBMCs) in venous blood from healthy donors were isolated by Lymphoprep (Axis-Shield, Norway). Human monocytes in PBMCs, identified as cells that expressed CD14, were enriched by positive immunomagnetic selection using anti-CD14 MicroBeads (Miltenyi, Germany). TEMs (TIE2+CD14+) and TIE2-Monocytes (Tie2-CD14+) were then isolated by FACS-sorting (Aria II, BD Biosciences) using FITC-conjugated anti-CD14 (BD Biosciences, USA) and APC-conjugated anti-TIE2 (R&D System, USA) antibodies.Three TEMs samples together with their paried TIE2-Monocytes were detected.Expressions of sixteen genes (CDKN1A, FDXR, SESN1, BBC3 and PHPT1) from this signature was quantified in the same RNA samples by real-time PCR, confirming low variability between donors as well as the predicted radiation response pattern.
2017-05-17 | GSE57783 | GEO
Project description:To identify the miRNA expressing profiles of TIE2 expressing Monocytes (TEMs), we have employed the Agilent Human miRNA 8×60K (Design ID:046064) microarray. Human peripheral blood mononuclear cells (PBMCs) in venous blood from healthy donors were isolated by Lymphoprep (Axis-Shield, Norway). Human monocytes in PBMCs, identified as cells that expressed CD14, were enriched by positive immunomagnetic selection using anti-CD14 MicroBeads (Miltenyi, Germany). TEMs (TIE2+CD14+) and TIE2-Monocytes (Tie2-CD14+) were then isolated by FACS-sorting (Aria II, BD Biosciences) using FITC-conjugated anti-CD14 (BD Biosciences, USA) and APC-conjugated anti-TIE2 (R&D System, USA) antibodies.Three TEMs samples together with their paried TIE2-Monocytes were detected.
2017-05-19 | GSE68322 | GEO
Project description:To identify the gene expressing profiles of TIE2 expressing Monocytes(TEMs), we have employed the Agilent lncRNA Gene Expression 4Ã180K(Design ID:042818) microarray. Human peripheral blood mononuclear cells (PBMCs) in venous blood from healthy donors were isolated by Lymphoprep (Axis-Shield, Norway). Human monocytes in PBMCs, identified as cells that expressed CD14, were enriched by positive immunomagnetic selection using anti-CD14 MicroBeads (Miltenyi, Germany). TEMs (TIE2+CD14+) and TIE2-Monocytes (Tie2-CD14+) were then isolated by FACS-sorting (Aria II, BD Biosciences) using FITC-conjugated anti-CD14 (BD Biosciences, USA) and APC-conjugated anti-TIE2 (R&D System, USA) antibodies.Three TEMs samples together with their paried TIE2-Monocytes were detected.Expressions of sixteen genes (CDKN1A, FDXR, SESN1, BBC3 and PHPT1) from this signature was quantified in the same RNA samples by real-time PCR, confirming low variability between donors as well as the predicted radiation response pattern. The gene expressions of three independent paried TEMs and TIE2- Monocytes samples from different donors were measured.
2017-05-17 | E-GEOD-57783 | biostudies-arrayexpress
Project description:To investigate chromatin accessibility in peri-infarct neurons on day 4 after ischemic stroke, we performed assay for transposase-accessible chromatin with sequencing (ATAC-seq) in peri-infarct neurons from Padi4 non-dificient mice.
2023-07-24 | GSE232169 | GEO
Project description:The addition of anti-angiogenic therapy to the few treatments available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on encouraging results from preclinical and clinical studies. However, tumors that initially respond to this therapy invariably recur with the acquisition of a highly aggressive and invasive phenotype. Although several myeloid populations have been associated to this pattern of recurrence, a specific targetable population has not been yet identified. Here, we present evidence for the accumulation of Tie2-expressing monocytes/macrophages (TEMs) at the tumor/normal brain interface of mice treated with anti-VEGF therapies in regions with heightened tumoral invasion. Furthermore, we describe the presence of TEMs in malignant glioma surgical specimens that recurred after bevacizumab treatment. Our studies showed that TEMs enhanced the invasive properties of glioma cells and secreted high levels of gelatinase enzymatic proteins. Accordingly, Tie2?MMP9? monocytic cells were consistently detected in the invasive tumor edge upon anti-VEGF therapies. Our results suggest the presence of a specific myeloid/monocytic subpopulation that plays a pivotal role in the mechanism of escape of malignant gliomas from anti-VEGF therapies and therefore constitutes a new cellular target for combination therapies in patients selected for anti-angiogenesis treatment.
| S-EPMC4039157 | biostudies-literature
Project description:To investigate distribution of histone-H3-citrullinated sites in peri-infarct neurons on day 4 after ischemic stroke and sham-operated mice, we performed cleavage under targets and tagmentation (CUT&Tag) assay for citrullinated histone H3 of peri-infarct neurons from Padi4-dificient or control mice .
2023-07-24 | GSE232171 | GEO