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.
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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

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Figure 6

Tet2-mediated clonal hematopoiesis accelerates age-related cardiomyopathy.

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Tet2-mediated clonal hematopoiesis accelerates age-related cardiomyopat...
(A) Schematic of this study. A total of 1.5 × 107 unfractionated donor bone marrow cells were sequentially injected into non-preconditioned B6 CD45.1 Pep Boy recipients. Donor cells were obtained from either C57BL/6J WT mice (Tet2+/+) or Tet2-deficient mice (Tet2–/–). Echocardiography was performed at the indicated time points. Mice were euthanized for the analysis 18 months after BMT. (B) Flow cytometry analysis of immune cells in the heart shows increased chimerism of donor-derived cardiac immune cells in mice transplanted with Tet2-deficient cells (n = 7–10 per genotype). Statistical analysis was performed with 2-tailed unpaired Student’s t test (Neut) and Mann-Whitney U tests (Ly6Chi mono, Total mac). (C) Data of sequential echocardiography analysis to show progressive decrease in cardiac function in mice with Tet2-mediated clonal hematopoiesis (n = 7–10 per genotype). Statistical analysis was performed with 2-way repeated-measures ANOVA with Holm-Šídák multiple-comparisons tests. (D) Tail cuff–measured blood pressure of each group at study end to show no obvious difference in each group (n = 7–10 per genotype). Statistical analysis was performed with 2-tailed unpaired Student’s t test. (E) Representative data of histological analysis of the heart from mice transplanted with Tet2-sufficient and -deficient bone marrow cells at the end of study. Scale bar: 600 μm. (F) Heart weight of the mice from each group (n = 7–10 per genotype). Statistical analysis was performed with 2-tailed unpaired Student’s t test. (G) Cross-sectional area (CSA) in left ventricles 18 months after BMT was assessed by wheat germ agglutinin staining from heart of Tet2+/+ BMT (n = 10) mice and Tet2–/– BMT mice (n = 7). Staining shows that the heart displays greater hypertrophy of the cardiac myocytes in Tet2–/– BMT mice. Statistical analysis was performed with 2-tailed unpaired Student’s t test. (H) Quantitative analysis of cardiac sections stained with Picrosirius red showing that mice with Tet2-mediated clonal hematopoiesis exhibit enhanced fibrosis (n = 7–10 per genotype). Statistical analysis was performed with 2-tailed unpaired Student’s t test. *P < 0.05, ***P < 0.001, and ****P < 0.0001.