Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction

ABSTRACT: Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We used a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2- mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models the human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.

ORGANISM(S): Mus musculus

PROVIDER: GSE146812 | GEO | 2020/03/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Effect of common mutations in clonal hematopoiesis of indeterminate potential (CHIP) on the transcriptome in bone marrow derived macrophages (BMDM).

Project description:Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of inflammatory conditions, including cardiovascular disease, in humans. The goal of the present data set was to examine the molecular mechanism underlying the increase in inflammation seen with the two most common CHIP mutations, namely loss-of-function mutations in Dnmt3a and Tet2, using murine bone-marrow derived macrophages (BMDM) as a model system.

2023-07-26 | GSE237599 | GEO

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Project description:Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to Tet2 mutation. Cell differentiation stage also influenced Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitized cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.

1970-01-01 | MTBLS9914 | MetaboLights

Tet2 loss dysregulates the behavior of bone marrow derived mesenchymal stromal cells

Project description:TET2 plays an important role in regulating the behavior of bone marrow derived MSCs in addition to its intrinsic role in HSPCs to participate in aberrant hematopoiesis. Moreover, MSCs are the most important niche cell components in Tet2-/- mice that contribute to the progression of Tet2 deletion-driven myeloid malignancies. This SuperSeries is composed of the SubSeries listed below.

2018-02-13 | GSE100073 | GEO

TET2-mutant clonal hematopoiesis and risk of gout

Project description:TET2-mutant clonal hematopoiesis and risk of gout

| PRJNA848666 | ENA

Nanostring immune profiling of air and cigarette smoke exposed wildtype bone marrow hematopoietic cells and Nanostring immune profiling of air and cigarette smoke exposed bone marrow hematopoietic cells from mice containing Jak2V617F mutant cells

Project description:Extrinsic stressors must have a role in driving clonal hematopoiesis since only a fraction of individuals with clonal hematopoiesis of indeterminate potential (CHIP) develop hematologic malignancy. Smoking behavior is associated with CHIP, but the effects of cigarette smoke on hematopoietic stem cells (HSCs) are unknown. The exploding use of electronic (E)-cigarettes has led to significant concern on their health effects. In this project, we aimed to determine the impact of cigarette smoke on the frequency and numbers of HSCs and inflammatory gene expression changes in bone marrow hematopoietic cells using wildtype mice. We also determined if cigarette smoke drives clonal expansion in mosaic mice containing both wildtype and Jak2V617F mutant cells. We also performed gene expression profiling on the wildtype fraction of bone marrow hematopoietic cells from mosaic mice exposed to cigarette smoke or air to determine if the presence of mutant cells alters the signature of wildtype cells.

2023-12-01 | E-MTAB-13133 | biostudies-arrayexpress

RNA-Seq of TET2 uniallelic mutated and wild type CFU colonies from rhesus macaque HSPCs

Project description:Gene expression profile of individual CFU-GM colonies identified as uniallelic TET2 mutant versus TET2 wild type was analyzed via RNA-Seq to verify the impact of TET2 editing on gene expression in the rhesus macaque clonal hematopoiesis model.

2022-06-22 | GSE148132 | GEO

Bone marrow adipocytes fuel emergency hematopoiesis

Project description:Hematopoiesis advances cardiovascular disease by generating inflammatory leukocytes that attack the arteries, heart and brain. While it is well documented that the bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, it is less clear how cardiovascular disease affects the vasculature forming this niche. Here we show that arterial hypertension, atherosclerosis and myocardial infarction alter the anatomy and function of bone marrow vasculature. Hypertension and atherosclerosis instigated vascular fibrosis, leakage and endothelial dysfunction in the bone marrow. Myocardial infarction induced vascular leakage and bone marrow angiogenesis via Vegf signaling. Endothelial cell-specific deletion of the Vegf receptor 2 limited emergency hematopoiesis after myocardial infarction, indicating that new vasculature supports higher blood cell production. RNA-sequencing of bone marrow endothelial cells revealed inflammatory gene expression in mice with cardiovascular disease. Endothelial cell-specific deletion of interleukin 6 or versican, which were highly expressed in mice with atherosclerosis or myocardial infarction, respectively, reduced hematopoiesis and systemic myeloid cells. Taken together, cardiovascular disease affects the vascular bone marrow niche, thus influencing hematopoietic stem cell behavior and expanding innate immune cell supply to atherosclerotic plaque and ischemic myocardium. Interrupting this feed back loop may constrain cardiovascular inflammation.

2023-11-04 | GSE169267 | GEO

Cardiovascular disease perturbs the vascular hematopoietic stem cell niche

2021-09-27 | GSE144498 | GEO

RNA seq analysis of calcium channel blocker, nifedipine in combination with metformin, MCC950 and anakinra treated Tet2-/- + Boy/J (1:1 ratio, mixed BM cells) transplanted Ob/Ob recipient mice

Project description:Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis (CH) of indeterminate potential (CHIP) involves expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy and cardiovascular disease (CVD). However, risk factors that contribute to CHIP-associated CH are poorly understood. A common, pro-inflammatory comorbidity responsible for enhancing the risk for developing type 2 diabetes mellitus (T2DM), CVD and cancer, obesity may exacerbate CHIP-associated diseases. We analyzed exome sequencing and clinical data from 47,466 individuals with valid CHIP in the UK Biobank. CHIP was present in 5.8% of the study population, and was associated with a significant increase in waist-to-hip ratio (WHR). The cancer genome atlas (TCGA) interrogation revealed that the mutation rate of CHIP is higher in patients with high BMI (>30 kg/m2) compared to those with low BMI (≤25 kg/m2) in six different cancer types. Utilizing mouse models of obesity bearing CHIP mutations, we show that both the compound mutant mice (Tet2-/-;Ob/Ob, Dnmt3a+/-;Ob/Ob) and CHIP mutant bone marrow (BM; Tet2-/-, Dnmt3a+/-, Asxl1+/- and Jak2+/-) transplanted into Ob/Ob mice develop rapid CH, leading to severe MPN/AML as well as CVD, which among other things, is associated with upregulation of intracellular calcium (Ca2+) levels and pro-inflammatory cytokines. Remarkably, calcium channel blocker nifedipine, in combination with metformin, MCC950 and anakinra, suppressed the growth of mutant CHIP cells, cardiovascular disease and restored normal hematopoiesis as well as serum Ca2+ and inflammatory cytokines. Thus, obesity is highly associated with the presence of CHIP and targeting CHIP mutant cells with a combination of metformin/nifedipine/MCC950/anakinra is a safe and inexpensive approach to treat CH and its associated abnormalities in obese individuals.

2022-01-08 | GSE193062 | GEO

Changes in the Bone Marrow Microenvironment Impact Anabolic Actions of PTH

Project description:Irradiation induced bone marrow ablation ultimately enhanced PTH anabolic effects in bone. B6 mice at 10 days of age were sub-lethally irradiated and treated with PTH 24h later for 5 days. 24h post last-injection, bone marrow was flushed with Trizol and RNA isolated and purified. Microarray analyses was performed to determine differential differences in PTH effects in non-irradiated vs. irradiated bone marrow. Triplicates of 4 groups (total of 12 samples) which include: Nonirradiated Vehicle, Nonirradiated PTH, Irradiated Vehicle and Irradiated PTH

2011-09-29 | E-GEOD-28819 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data