TY - JOUR AU - Wang, Ying AU - Sano, Soichi AU - Yura, Yoshimitsu AU - Ke, Zhonghe AU - Sano, Miho AU - Oshima, Kosei AU - Ogawa, Hayato AU - Horitani, Keita AU - Min, Kyung-Duk AU - Miura-Yura, Emiri AU - Kour, Anupreet AU - Evans, Megan A. AU - Zuriaga, Maria A. AU - Hirschi, Karen K. AU - Fuster, Jose J. AU - Pietras, Eric M. AU - Walsh, Kenneth T1 - Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction PY - 2020/03/26/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.135204 VL - 5 IS - 6 UR - https://doi.org/10.1172/jci.insight.135204 PB - The American Society for Clinical Investigation ER -