Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction
Open Access
- 26 March 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
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 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.Keywords
Funding Information
- National Institutes of Health (HL131006,HL132564,HL138014)
- American Heart Association (17POST33670076)
- National Institutes of Health (R01 DK119394)
- Ramón y Cajal program of the Spanish Ministerio de Ciencia, Innovación y Universidades (RYC-2016-20026)
- Severo Ochoa Center of Excellence (SEV-2015-0505)
- Kanae Foundation for the Promotion of Medical Science (404891)
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