MiR-126-driven Vascular Remodeling of Aging Bone Marrow: A Correctable Cause of Age-related Loss of Hematopoietic Activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE296123 | GEO | 2025/05/06
REPOSITORIES: GEO
Similar Datasets
Project description:Life-long blood cell production is governed through the poorly understood integration of cell-intrinsic and -extrinsic control of hematopoietic stem cell (HSC) quiescence and activation. MicroRNAs (miRNAs) coordinately regulate multiple targets within signaling networks making them attractive candidate HSC regulators. We report that miR-126, a miRNA expressed in HSC and early progenitors, plays a pivotal role in restraining cell cycle progression of HSC in vitro and in vivo. miR-126 knockdown using lentiviral sponges increased HSC proliferation without inducing exhaustion, resulting in expansion of mouse and human long-term repopulating HSC. Conversely, enforced miR-126 expression impaired cell cycle entry leading to progressively reduced hematopoietic contribution. In HSC/early progenitors, miR-126 regulates multiple targets within the PI3K/AKT/GSK3β pathway thus attenuating signal transduction in response to extrinsic signals. These data establish that miR-126 sets a threshold for HSC activation and thus governs HSC pool size, demonstrating the importance of miRNA in the control of HSC function.
2012-11-30 | GSE40458 | GEO
Project description:Life-long blood cell production is governed through the poorly understood integration of cell-intrinsic and -extrinsic control of hematopoietic stem cell (HSC) quiescence and activation. MicroRNAs (miRNAs) coordinately regulate multiple targets within signaling networks making them attractive candidate HSC regulators. We report that miR-126, a miRNA expressed in HSC and early progenitors, plays a pivotal role in restraining cell cycle progression of HSC in vitro and in vivo. miR-126 knockdown using lentiviral sponges increased HSC proliferation without inducing exhaustion, resulting in expansion of mouse and human long-term repopulating HSC. Conversely, enforced miR-126 expression impaired cell cycle entry leading to progressively reduced hematopoietic contribution. In HSC/early progenitors, miR-126 regulates multiple targets within the PI3K/AKT/GSK3β pathway thus attenuating signal transduction in response to extrinsic signals. These data establish that miR-126 sets a threshold for HSC activation and thus governs HSC pool size, demonstrating the importance of miRNA in the control of HSC function. Total RNA was extracted from cord blood Lin- cells and treated with mir126 shRNA or mir126 containing viral particles (and corresponding controls)
2012-11-30 | E-GEOD-40458 | biostudies-arrayexpress
Project description:"The analysis was designed to search for putative seed sequences for miR-126 in the 3’UTR of up-regulated genes. ECs were co-transfected with anti-miR-126 and a plasmid vector bearing the GFP-coding sequence and three complementary sites for miR-126 downstream. As a consequence of the presence of miR-126 binding sites the GFP expression was under the control of miR-126. Fluorescente cells were the cells transfected with anti-miR-126 oligo. MiR-126 target enrichment analysis was performed on the basis of the Miranda database, as provided by Diana miRGen. Significance was estimated on the basis of hyper geometric distribution p-values comparing the occurrence of miR targets in the signature with respect to the universe, defined as the genes expressed in HUVEC. Frequency of log 2 ratio between the subset of mir-126 targets and the genes which are not targets of miR-126 were plotted, highlighting enrichment of the target of miR in differentially regulated genes. "
2013-10-18 | GSE32089 | GEO
Project description:"The analysis was designed to search for putative seed sequences for miR-126 in the 3M-bM-^@M-^YUTR of up-regulated genes. ECs were co-transfected with anti-miR-126 and a plasmid vector bearing the GFP-coding sequence and three complementary sites for miR-126 downstream. As a consequence of the presence of miR-126 binding sites the GFP expression was under the control of miR-126. Fluorescente cells were the cells transfected with anti-miR-126 oligo. MiR-126 target enrichment analysis was performed on the basis of the Miranda database, as provided by Diana miRGen. Significance was estimated on the basis of hyper geometric distribution p-values comparing the occurrence of miR targets in the signature with respect to the universe, defined as the genes expressed in HUVEC. Frequency of log 2 ratio between the subset of mir-126 targets and the genes which are not targets of miR-126 were plotted, highlighting enrichment of the target of miR in differentially regulated genes. " 3 x biological replicates of transiently trasfected cells with anti miR-126 oligo (LNA), and controls oligo. 2 biological replicates for GFP are included as technical controls.
2013-10-18 | E-GEOD-32089 | biostudies-arrayexpress
Project description:The pathways involved in hierarchical differentiation of human embryonic stem cells (hESC) into abundant and durable endothelial cells (EC) are unknown. We employed an EC-specific VE-cadherin promoter driving GFP (hVPr-GFP) to screen for factors that augmented yields of vascular-committed ECs from hESCs. In phase 1 of our approach, inhibition of TGFb, precisely at day 7 of hESC differentiation, enhanced emergence of hVPr-GFP+ ECs by 10-fold. In the second phase, TGFb-inhibition preserved proliferation and vascular identity of purified ECs, resulting in net 36-fold expansion of homogenous EC-monolayers, and allowing transcriptional profiling that revealed a unique angiogenic signature defined by the VEGFR2highId1highVE-cadherin+EphrinB2+CD133+HoxA9- phenotype. Using an Id1-YFP hESC reporter line, we showed that TGFb-inhibition sustained Id1 expression in hESC-derived ECs, which was required for increased proliferation and preservation of EC commitment. These data provide a multiphasic method for serum-free differentiation and long-term maintenance of authentic hESC-derived ECs, establishing clinical-scale generation of transplantable human ECs. The experiment compared 6 sets of biological duplicates which included human embryonic stem cell derived and mature vascular cell types.
2010-01-05 | E-GEOD-19735 | biostudies-arrayexpress
Project description:Pluripotent stem cells (PSC) represent an alternative source of hematopoietic stem cells (HSCs). Clinical translation is impeded by limited engraftment of human (h)PSC-multipotent progenitor cells (MPP). This barrier suggests that additional cues are required for definitive hematopoiesis. We hypothesized that vascular niche producing Notch ligands Jagged-1 (JAG1) and Delta-like ligand-4 (DLL4) would drive definitive hematopoiesis. To test our hypothesis, hes2 human embryonic stem cells (hESC) 2 and Macaca nemestrina (Mn) iPSC line-7 were differentiated with cytokines ± endothelial cells (EC), which express JAG1 and DLL4. EC co-culture supported emergence of 8-fold more CD34+CD45+ cells compared to co-culture with cytokines ± ECs with JAG1 or DLL4 knockdown. EC-induced cells exhibit Notch activation and express HSC-specific targets of Notch signaling RUNX1 and GATA2. EC-induced PSC-MPP engraft at a higher level in NSG mice compared to cytokine-induced cells (10% >5 months), and selection increased engraftment (30%). Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction is similar to levels achieved for cord blood MPP and up to 20-fold higher than hPSC-MPP engraftment. Our findings identify a previously underappreciated role for endothelial Notch ligands in PSC definitive hematopoiesis and production of long-term engrafting CD34+ cells and suggest they are critical for HSC emergence. Transcriptome sequencing of Macaca nemestrina (Mn) iPSCs
2015-12-31 | E-GEOD-64644 | biostudies-arrayexpress
Project description:Based on microRNA expression profiling studies, here we focus on miR-126&126* as the most downmodulated microRNAs in a panel of melanoma cell lines at different stages of progression compared with normal human melanocytes. At present no data exist on miR-126&126* possible role in melanoma. Our results show miR-126/miR-126* downregulation associated with tumor progression and the antineoplastic role deriving from their restored expression in metastatic melanomas in vitro as well as in vivo.
2013-05-21 | E-MEXP-3629 | biostudies-arrayexpress
Project description:Aging significantly affects intercellular communication between vascular endothelial cells (ECs) and hematopoietic cells, leading to vascular inflammation and age-associated diseases. This study determined how senescent ECs communicate with monocytes, whether extracellular vesicles (EVs) released from senescent ECs affect monocyte functions, and investigated the potential for epigallocatechin-3-gallate (EGCG), a flavonoid in green tea, to reverse these effects. Human umbilical vein endothelial cells (HUVECs) were treated with Etoposide (10 µM, 24h) to induce senescence, followed by EGCG (100 µM, 24h) treatment to evaluate its potential as a senotherapeutic agent. The interaction between ECs and monocytes was analyzed using a co-culture system and direct treatment of monocytes with EC-derived EVs. EGCG reduced senescence-associated phenotypes in ECs, as evidenced by decreased senescence-associated (SA)-β-Gal activity and reversal of Etoposide-induced senescence markers. Monocytes co-cultured with EGCG-treated senescent ECs showed decreased pro-inflammatory responses compared to those co-cultured with untreated senescent ECs. Additionally, senescent ECs produced more EVs than non-senescent ECs. EVs from senescent ECs enhanced lipopolysaccharide (LPS)-induced pro-inflammatory activation of monocytes, whereas EVs from EGCG-treated senescent ECs mitigated this activation, maintaining monocyte activation at normal levels. Our findings reveal that EGCG confers anti-senescent effects via modulation of the senescent EC secretome (including EVs) with the capacity to modify monocyte activation. These findings suggest that EGCG could act as a senotherapeutic agent to reduce vascular inflammation related to aging.
2025-01-18 | GSE286438 | GEO
Project description:Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduced AML rate and extended survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibited AML cell survival, reduced leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. Combination of miRisten with chemotherapy further enhanced the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a new therapeutic approach for inv(16) AML.
2021-09-15 | GSE184015 | GEO
Project description:The goal of this study is to investigate the cell type-specific targets of miR-126-3p in human lung microvascular endothelial cells (HLMVEC). Following the transfections of HLMVEC with non-targeting negative controls, miR-126 mimics, or miR-126 antisense inhibitors, we calculated the copy number concentration of miR-126 in each sample and performed genome-wide RNA sequencing. Plotting the gene expression data for each transfection condition (Scramble, 126-OE and 126-KD) against their respective miR-126 concentrations, we performed a linear regression analysis to discover genes that were the most sensitive to changes in miR-126 levels. We identified 1258 genes that were upregulated and 1436 genes that were downregulated by miR-126-3p. Further comparison between the downregulated genes in HLMVEC and targets predicted by online databases including TargetScan and miRDB revealed 6 genes as potential direct targets of miR-126-3p. Our study is the first to report targets of miR-126-3p in HLMVEC and demonstrate the effect of miR-126 level alteration on the HLMVEC global transcriptome. These results add to the diverse functions of miR-126-3p in different endothelial cell types and provide basis for the development of cell type-specific treatment for lung diseases.
2022-11-27 | GSE141129 | GEO