Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction
Wang, Y., S. Sano, Y. Yura, Z. Ke, M. Sano, K. Oshima, H. Ogawa, K. Horitani, K-D. Min, E. Miura-Yura,
A. Kour, M.A. Evans, M.A. Zuriaga, K.K. Hirschi, J.J. Fuster, E.M. Pietras and K. Walsh. (2020) Tet2-mediated clonal hematopoiesis in non-conditioned mice accelerates age-associated cardiac dysfunction.
JCI Insight 5(6):e135204. doi.org/10.1172/jci.insight.135204.
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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