Tet2-mediated clonal hematopoiesis in non-conditioned mice accelerates age-associated cardiac dysfunction.

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 employed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2 (Tet2)-deficient bone marrow cells into non-irradiated 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 linages. The expansion of the Tet2 mutant fraction was also observed in bone marrow-derived CCR2+ myeloid cell populations within the heart, but there was 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-deficient hematopoiesis contributes to cardiac dysfunction in a non-conditioned 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.

• Publication year

  2020

• Venue

  JCI Insight

• Publication date

  2020-03-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1172/jci.insight.135204PMID 32154790PMCID PMC7213793
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• New Approaches to Target Inflammation in Heart Failure: Harnessing Insights from Studies of Immune Cell Diversity.

  2020cited by this paper
• Age-related clonal haemopoiesis is associated with increased epigenetic age

  2019cited by this paper
• Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches

  2019cited by this paper
• Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping.

  2019cited by this paper
• Tissue Resident CCR2− and CCR2+ Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury

  2019cited by this paper
• Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

  2019cited by this paper
• JAK2V617F-Mediated Clonal Hematopoiesis Accelerates Pathological Remodeling in Murine Heart Failure

  2019cited by this paper
• Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation

  2019cited by this paper
• From discoveries in ageing research to therapeutics for healthy ageing

  2019cited by this paper
• Wnt5a-Mediated Neutrophil Recruitment Has an Obligatory Role in Pressure Overload-Induced Cardiac Dysfunction.

  2019cited by this paper
• Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis

  2019cited by this paper
• WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs

  2019cited by this paper
• Clonal Hematopoiesis and Its Impact on Cardiovascular Disease.

  2018cited by this paper
• Age-related clonal hematopoiesis.

  2018cited by this paper
• Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome.

  2018influential reference
• CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease

  2018cited by this paper
• Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A.

  2018cited by this paper
• Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease

  2018cited by this paper
• The Human Heart Contains Distinct Macrophage Subsets with Divergent Origins and Functions

  2018cited by this paper
• Insights about clonal hematopoiesis from 8,342 mosaic chromosomal alterations

  2018cited by this paper
• Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis.

  2018cited by this paper
• Clonal Hematopoiesis : a Common Condition in the Elderly Population

  2018cited by this paper
• Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis.

  2018cited by this paper
• Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

  2018cited by this paper
• Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure

  2018cited by this paper
• Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo

  2018cited by this paper
• Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease

  2017cited by this paper
• Different Sequences of Fractionated Low-Dose Proton and Single Iron-Radiation-Induced Divergent Biological Responses in the Heart

  2017cited by this paper
• Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.

  2017cited by this paper
• Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

  2017influential reference
• Clonal analysis of lineage fate in native hematopoiesis

  2017cited by this paper
• Numerous niches for hematopoietic stem cells remain empty during homeostasis.

  2017cited by this paper
• Single Targeted Exon Mutation Creates a True Congenic Mouse for Competitive Hematopoietic Stem Cell Transplantation: The C57BL/6-CD45.1STEM Mouse

  2016cited by this paper
• Follistatin‐like 1 promotes cardiac fibroblast activation and protects the heart from rupture

  2016cited by this paper
• Near-optimal probabilistic RNA-seq quantification

  2016cited by this paper
• Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions.

  2015influential reference
• Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.

  2015cited by this paper
• Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury*♦

  2015cited by this paper
• Clonal dynamics of native haematopoiesis

  2014cited by this paper
• Progressive replacement of embryo-derived cardiac macrophages with age

  2014cited by this paper
• Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation.

  2014influential reference
• Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.

  2014cited by this paper
• Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.

  2014cited by this paper
• Age-related clonal hematopoiesis associated with adverse outcomes.

  2014cited by this paper
• Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis.

  2014influential reference
• Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease

  2012cited by this paper
• Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation.

  2011cited by this paper
• Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine

  2011influential reference
• Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy.

  2011cited by this paper
• Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2

  2010influential reference
• Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity.

  2008cited by this paper
• Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure.

  2005cited by this paper
• Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2–dependent mechanisms

  2005cited by this paper
• Engraftment of normal murine marrow into nonmyeloablated host mice.

  1994cited by this paper

• TET2 loss enhances early response to inflammation in primitive and committed myeloid cells.

  2026cites this paper
• Epigenetic regulation of cardiac physiology and pathophysiology: biological sex matters

  2026cites this paper
• Oridonin as a novel KDM5C inhibitor alleviates clonal hematopoiesis-induced cardiac aging via H3K4me3-dependent SASP suppression

  2026cites this paper
• Empagliflozin Attenuates Cardiac Fibrosis by Suppressing Fibroblast-Mediated C-C Motif Chemokine Ligand 2 Expression.

  2026cites this paper
• The Immunological Consequences of Clonal Hematopoiesis in Heart Failure

  2026influential citation
• Ageing Through the Looking-Glass: The Different Flavours of Clonal Haematopoiesis.

  2026cites this paper
• Clonal Hematopoiesis in Nonmalignant Disease: Functional Consequences of Mutated Immune Cells by Clonal Hematopoiesis in the Diseased Tissue.

  2025cites this paper
• Clonal Hematopoiesis and Cardiovascular Outcomes in Older Women

  2025cites this paper
• Clonal Hematopoiesis in Cancer and Cardiovascular Disease

  2025cites this paper
• Prospective characterization of clonal hematopoiesis and its clinical associations in elderly patients

  2025cites this paper
• Clonal Hematopoiesis and Incident Heart Failure.

  2025cites this paper
• Cell-autonomous and non-cell-autonomous effects of Arginase 2 on cardiac aging

  2025cites this paper
• Clonal Haematopoiesis of Indeterminate Potential: a Unifying Mechanism Linking Meta-inflammation and Cardiometabolic Diseases.

  2025cites this paper
• Elevated clonal hematopoiesis in 9/11 first responders has distinct age-related patterns and relies on IL1RAP for clonal expansion.

  2025cites this paper
• HiJAKing the Hematopoietic System: A Low-Frequency JAK2V617F Clone Drives Myeloproliferative Neoplasm Pathology.

  2025cites this paper
• Target practice: Opportunities for therapeutic intervention in CHIP and CCUS.

  2025cites this paper
• Macrophages: Subtypes, Distribution, Polarization, Immunomodulatory Functions, and Therapeutics

  2025cites this paper
• Modelling the ageing dependence of cancer evolutionary trajectories

  2025cites this paper
• Tet Methylcytosine Dioxygenase 3 Promotes Cardiovascular Senescence by DNA 5‐Hydroxymethylcytosine‐Mediated Sp1 Transcription Factor Expression

  2025cites this paper
• Multitargeted Reduction of Inflammation and Atherosclerosis in Tet2-deficient CHIP via XPO1 Inhibition and Atf3 restoration

  2025cites this paper
• The crosstalk between immune activation and metabolism in heart failure. A scientific statement of the Heart Failure Association of the ESC

  2025cites this paper
• Contributions of Noncardiac Organ–Heart Immune Crosstalk and Somatic Mosaicism to Heart Failure: Current Knowledge and Perspectives

  2025cites this paper
• Clonal haematopoiesis in cardiovascular disease: prognostic role and novel therapeutic target

  2025cites this paper
• Clonal hematopoiesis of indeterminate potential: contribution to disease and promising interventions

  2025cites this paper
• TET2 deficiency increases the competitive advantage of hematopoietic stem and progenitor cells through upregulation of thrombopoietin receptor signaling

  2025cites this paper
• Association of clonal haematopoiesis with heart failure incidence and outcomes: A systematic review and meta‐analysis

  2025cites this paper
• Revolutionising Cardio-Oncology Care with Precision Genomics

  2025cites this paper
• Association of clonal hematopoiesis of indeterminate potential with myocardial characteristic differences in non-ischemic heart failure

  2025cites this paper
• A non-conditioned bone marrow transplantation mouse model to study clonal hematopoiesis and myeloid malignancies

  2025cites this paper
• Geroscience in heart failure: the search for therapeutic targets in the shared pathobiology of human aging and heart failure

  2025cites this paper
• Functional diversity of cardiac macrophages in health and disease

  2025cites this paper
• Id1 promotes clonal hematopoiesis in mice with Tet2 loss of function

  2025cites this paper
• Cell-autonomous and non-cell-autonomous effects of arginase-II on cardiac aging

  2025cites this paper
• Evolution of myeloproliferative neoplasms from normal blood stem cells

  2024cites this paper
• Clonal Hematopoiesis and Risk of Heart Failure After Autologous Hematopoietic Cell Transplantation for Lymphoma

  2024cites this paper
• Clonal Hematopoiesis in Chronic Thromboembolic Pulmonary Hypertension

  2024cites this paper
• Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

  2024cites this paper
• Pathogenesis and inflammaging in myelodysplastic syndromes

  2024cites this paper
• The emerging role of clonal haematopoiesis in the pathogenesis of dilated cardiomyopathy

  2024cites this paper
• Epigenetic Regulation in Myocardial Fibroblasts and Its Impact on Cardiovascular Diseases

  2024cites this paper
• Salt and CHIP: Tet2-CH Aggravates Salt-Sensitive Hypertension in Mice.

  2024cites this paper
• Experimental TET2 Clonal Hematopoiesis Predisposes to Renal Hypertension Through an Inflammasome-Mediated Mechanism

  2024cites this paper
• Ultralow-dose irradiation enables engraftment and intravital tracking of disease initiating niches in clonal hematopoiesis

  2024influential citation
• Clinical and Therapeutic Implications of Clonal Hematopoiesis.

  2024cites this paper
• Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy.

  2024cites this paper
• Anti-ageing interventions for the treatment of cardiovascular disease

  2024cites this paper
• Age-associated clonal B cells drive B cell lymphoma in mice

  2024cites this paper
• Dynamics of clonal hematopoiesis and risk of hematologic malignancy

  2024cites this paper
• Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy

  2024cites this paper
• Decoding Clonal Hematopoiesis: Emerging Themes and Novel Mechanistic Insights

  2024cites this paper
• Systemic aging fuels heart failure: Molecular mechanisms and therapeutic avenues

  2024cites this paper
• Interplay of the heart, spleen, and bone marrow in heart failure: the role of splenic extramedullary hematopoiesis

  2024cites this paper
• Disruption of the Uty epigenetic regulator locus in hematopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure

  2024cites this paper
• Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1.

  2024cites this paper
• Solid organ transplant recipients exhibit more TET2-mutant clonal hematopoiesis of indeterminate potential not driven by increased transplantation risk.

  2024cites this paper
• Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury

  2024cites this paper
• Exploring the intricate cross-talk between clonal expansion and the bone marrow niche

  2024cites this paper
• Herz und Blut: klonale Hämatopoese

  2024cites this paper
• Metabolic basis of cardiac dysfunction in cancer patients

  2024cites this paper
• Mineralocorticoid receptor promotes cardiac macrophage inflammaging

  2024cites this paper
• Clonal haematopoiesis and cardiac arrythmias: rhythm-altering mutations.

  2024cites this paper
• Coenzyme Q10 mitigates macrophage mediated inflammation in heart following myocardial infarction via the NLRP3/IL1β pathway

  2024cites this paper
• Tet2-mediated clonal hematopoiesis modestly improves neurological deficits and is associated with inflammation resolution in the subacute phase of experimental stroke

  2024cites this paper
• Clonal Hematopoiesis of Indeterminate Potential From a Heart Failure Specialist's Point of View

  2023cites this paper
• The transcriptional and epigenetic reprogramming associated with chronic IL1β-mediated expansion and myeloid priming in TET2 deficient stem and progenitor cells

  2023cites this paper
• Lymphoid clonal hematopoiesis: implications for malignancy, immunity, and treatment

  2023cites this paper
• Clonal Hematopoiesis: Connecting Aging and Inflammation in Atherosclerosis

  2023cites this paper
• Clonal Hematopoiesis and the Heart: a Toxic Relationship

  2023cites this paper
• Clonal haematopoiesis and dysregulation of the immune system

  2023cites this paper
• Inflammatory Mechanisms in Heart Failure with Preserved Ejection Fraction.

  2023cites this paper
• Obesity-induced inflammation exacerbates clonal hematopoiesis

  2023cites this paper
• Review of clonal hematopoiesis, subtypes and its role in neoplasia and different morbidities.

  2023cites this paper
• Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury

  2023cites this paper
• Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity

  2023cites this paper
• Clonal Expansion in Cardiovascular Pathology

  2023cites this paper
• Single-cell genomics in acquired bone marrow failure syndromes

  2023cites this paper
• Inhibition of protein arginine deiminase 4 prevents inflammation-mediated heart failure in arthritis

  2023cites this paper
• Early activation of inflammatory pathways in UBA1-mutated hematopoietic stem and progenitor cells in VEXAS

  2023cites this paper
• Clonal Hematopoiesis has Prognostic Value in Dilated Cardiomyopathy independent of Age and Clone Size.

  2023cites this paper
• Novel Insights into the Molecular Mechanisms of Atherosclerosis

  2023cites this paper
• Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction

  2023cites this paper
• The spectrum of glomerular and vascular kidney pathology associated with myeloproliferative neoplasms.

  2023cites this paper
• The role of cardiac resident macrophage in cardiac aging

  2023cites this paper
• Clonal haematopoiesis, ageing and kidney disease

  2023cites this paper
• Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial

  2023cites this paper
• Clonal hematopoiesis of indeterminate potential: implications for the cardiologists.

  2023cites this paper
• Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells

  2023cites this paper
• Regulators of clonal hematopoiesis and physiological consequences of this condition

  2023cites this paper
• [Influence of clonal hematopoiesis on non-hematological diseases and aging processes].

  2022cites this paper
• Einfluss der klonalen Hämatopoese auf nicht-hämatologische Erkrankungen und Alterungsprozesse

  2022cites this paper
• Aging drives Tet2+/− clonal hematopoiesis via IL-1 signaling

  2022cites this paper
• Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Disease.

  2022cites this paper
• Clonal Hematopoiesis, Somatic Mosaicism, and Age-Associated Disease.

  2022cites this paper
• CHIPing away the progression potential of CHIP: A new reality in the making.

  2022cites this paper
• Germline genomic and phenomic landscape of clonal hematopoiesis in 323,112 individuals

  2022cites this paper
• Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

  2022cites this paper
• The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging‐related disease

  2022cites this paper
• Therapy-Related Clonal Hematopoiesis: A New Link Between Cancer and Cardiovascular Disease.

  2022cites this paper
• COMPENDIUM ON BASIC MODELS OF CARDIOVASCULAR DISEASE Heart Failure With Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models

  2022cites this paper
• Clonal hematopoiesis: Mutation-specific adaptation to environmental change.

  2022cites this paper