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.
Highlights
Clonal hematopoiesis can result from the acquisition of somatic mutations in preleukemic driver genes in hematopoietic stem cells (HSCs)
We modeled the expansion of mutant HSC clones by performing competitive bone marrow transplantation (BMT) studies in mice that were subjected to a lethal dose of radiation [3,4,5,6]
Our previous studies of clonal hematopoiesis have used conventional BMT techniques involving high-dose irradiation of recipient mice to favor the engraftment of donor bone marrow cells [3,4,5,6]
Summary
Clonal hematopoiesis can result from the acquisition of somatic mutations in preleukemic driver genes in hematopoietic stem cells (HSCs). Mutations in the epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and ten-eleven translocation 2 (TET2) are frequently observed in individuals with clonal hematopoiesis in the absence of cytopenias and dysplastic hematopoiesis, a condition that has been referred to as clonal hematopoiesis of indeterminate potential or age-related clonal hematopoiesis [1, 2]. These mutations are thought to provide HSCs a competitive advantage within the bone marrow niche that leads to their clonal expansion. Clonal hematopoiesis generally does not lead to changes in total blood cell numbers, the leukocytes derived from these mutant clones can exhibit altered inflammatory properties [3,4,5,6,7,8,9]
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