PLX076626

GSE146812: Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

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. SOURCE: Anupreet Kour (ak5xu@virginia.edu) - Kenneth Walsh University of Virginia