Tet2-driven clonal hematopoiesis drives aortic aneurysm via macrophage-to-osteoclast–like differentiation
Jun Yonekawa, Yoshimitsu Yura, Junmiao Luo, Katsuhiro Kato, Shuta Ikeda, Yohei Kawai, Tomoki Hattori, Ryotaro Okamoto, Mari Kizuki, Emiri Miura-Yura, Keita Horitani, Kyung-Duk Min, Takuo Emoto, Hiroshi Banno, Mikito Takefuji, Kenneth Walsh, Toyoaki Murohara
Jun Yonekawa, Yoshimitsu Yura, Junmiao Luo, Katsuhiro Kato, Shuta Ikeda, Yohei Kawai, Tomoki Hattori, Ryotaro Okamoto, Mari Kizuki, Emiri Miura-Yura, Keita Horitani, Kyung-Duk Min, Takuo Emoto, Hiroshi Banno, Mikito Takefuji, Kenneth Walsh, Toyoaki Murohara
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Research Article Aging Cardiology Vascular biology

Tet2-driven clonal hematopoiesis drives aortic aneurysm via macrophage-to-osteoclast–like differentiation

Abstract

Aortic aneurysms are age-linked aortic dilations that progress silently and carry high mortality rates following rupture. Immune cells are recognized drivers of aneurysm pathogenesis. Clonal hematopoiesis is an age-related expansion of somatically mutated hematopoietic stem cells that reshapes immune function and contributes to diverse age-associated diseases. However, its contribution to aneurysm pathogenesis remains unclear. In this study, targeted ultradeep sequencing of patient specimens revealed a high prevalence of clonal hematopoiesis–associated mutations that correlated with faster aneurysm expansion. Thus, we modeled clonal hematopoiesis by competitively transplanting ten-eleven translocation 2–deficient (Tet2-deficient) bone marrow into apoliprotein E–KO (Apoe-KO) mice and induced aneurysms with angiotensin II. Mice with Tet2 clonal hematopoiesis developed significantly greater aortic dilation than did controls. Interestingly, Tet2-deficient macrophages adopted an acid phosphatase 5, tartrate resistant (ACP5+), osteoclast-like state and produced more matrix metalloproteinase 9 (MMP9). Both genetic and pharmacological inhibition of osteoclast-like differentiation suppressed the Tet2-mediated aneurysmal growth in vivo. Thus, Tet2-driven clonal hematopoiesis accelerated aortic aneurysm progression through MMP9-producing, osteoclast-like macrophages and therefore represents a tractable therapeutic axis.

Authors

Jun Yonekawa, Yoshimitsu Yura, Junmiao Luo, Katsuhiro Kato, Shuta Ikeda, Yohei Kawai, Tomoki Hattori, Ryotaro Okamoto, Mari Kizuki, Emiri Miura-Yura, Keita Horitani, Kyung-Duk Min, Takuo Emoto, Hiroshi Banno, Mikito Takefuji, Kenneth Walsh, Toyoaki Murohara

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Figure 1

Clonal hematopoietic mouse model shows greater aortic aneurysm formation in response to AngII infusion.

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Clonal hematopoietic mouse model shows greater aortic aneurysm formation...
(A) Schematic of AAA model establishment using Apoe-KO mice and AngII infusion. To model clonal hematopoiesis, mice received 80% WT and 20% Tet2-KO BM cells after irradiation. Control mice received 100% WT BM. (B) Absolute number of WBCs, RBCs, and platelets (PLTs) in both experimental groups (n = 8 per genotype). Statistical significance was evaluated using an unpaired, 2-tailed Welch’s t test. (C) Representative flow cytometric gating plots of peripheral blood 4 weeks after transplantation (n = 8 mice per genotype). (D) Quantification of peripheral blood cell populations 4 weeks after transplantation (n = 8 mice per genotype). ****P < 0.0001, by Mann-Whitney U test. (E) Systolic blood pressure (sBP) was measured using tail-cuff plethysmography after 1 week of AngII infusion (n = 8 mice per genotype). *P < 0.05, by 2-way, repeated-measures ANOVA with Šidák’s multiple-comparison test. (F) Representative ultrasound images of the abdominal aorta at 0 (baseline) and 4 weeks after AngII infusion. Images are representative of 8 mice per genotype. (G) Quantification of abdominal aortic diameter at 0 (baseline), 2, and 4 weeks after AngII infusion (n = 8 mice per genotype). *P < 0.05, by 2-way, repeated-measures ANOVA with Šidák’s multiple-comparison test. (H) Representative images of Elastica van Gieson staining of abdominal aortic tissue. Scale bars: 100 μm. (I) Elastin fiber thickness and rupture counts in H (n = 8 mice per genotype). *P < 0.05 and ****P < 0.0001, by 2-tailed, unpaired Student’s t test, and for rupture counts using a 2-tailed Mann-Whitney U test.