Journal
JCI INSIGHT
Volume 5, Issue 6, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.135204
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Funding
- NIH [HL131006, HL132564, HL138014]
- American Heart Association Postdoctoral Fellowship [17POST33670076]
- Kanae Foundation for the Promotion of Medical Science
- Ramon y Cajal program of the Spanish Ministerio de Ciencia, Innovacion y Universidades [RYC-2016-20026]
- Instituto de Salud Carlos III
- Ministerio de Ciencia, Innovacion y Universidades
- Pro CNIC Foundation
- [R01 DK119394]
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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 developed 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 CCR2(+) 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 human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.
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