Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction
Ying Wang, … , Eric M. Pietras, Kenneth Walsh
Ying Wang, … , Eric M. Pietras, Kenneth Walsh
Published March 10, 2020
Citation Information: JCI Insight. 2020;5(6):e135204. https://doi.org/10.1172/jci.insight.135204.
View: Text | PDF
Research Article Aging Cardiology

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

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.

Authors

Ying Wang, Soichi Sano, Yoshimitsu Yura, Zhonghe Ke, Miho Sano, Kosei Oshima, Hayato Ogawa, Keita Horitani, Kyung-Duk Min, Emiri Miura-Yura, Anupreet Kour, Megan A. Evans, Maria A. Zuriaga, Karen K. Hirschi, Jose J. Fuster, Eric M. Pietras, Kenneth Walsh

×

Figure 5

RNA-Seq analysis of Tet2-sufficient and Tet2-deficient donor-derived cardiac macrophages.

Options: View larger image (or click on image) Download as PowerPoint
RNA-Seq analysis of Tet2-sufficient and Tet2-deficient donor-derived car...
(A) Scheme of the study. Donor bone marrow–derived macrophages were defined as the CD45.2+CD64+Ly6G–Ly6C– population. At 8 months after adoptive transfer, 1363 cells were sorted from mice and used for ultralow-input RNA-Seq. (B) Principal component analysis of ultralow-input RNA-Seq data obtained from sorted donor bone marrow–derived cardiac macrophages of Tet2-sufficient and Tet2-deficient mice (n = 3 per genotype). (C) Volcano plots showing the number of genes differentially expressed between cardiac macrophages derived from WT versus Tet2-deficient bone marrow cells. (D) Heatmap of a select group of the most highly differentially expressed genes from the highest ranked annotation categories comparing cardiac macrophages derived from WT versus Tet2-deficient bone marrow cells. (E) Result of donor chimerism of cardiac subpopulations normalized by donor chimerism of peripheral blood Ly6Chi monocytes (n = 6 per genotype). Statistical analysis was performed with 2-tailed unpaired Student’s t test. *P < 0.05, and ****P < 0.0001.