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ResearchIn-Press PreviewAgingCardiologyVascular biology Open Access | 10.1172/JCI198708

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

Jun Yonekawa,1 Yoshimitsu Yura,1 Junmiao Luo,1 Katsuhiro Kato,1 Shuta Ikeda,2 Yohei Kawai,2 Tomoki Hattori,1 Ryotaro Okamoto,1 Mari Kizuki,1 Emiri Miura-Yura,3 Keita Horitani,4 Kyung-Duk Min,5 Takuo Emoto,6 Hiroshi Banno,2 Mikito Takefuji,1 Kenneth Walsh,7 and Toyoaki Murohara1

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Yonekawa, J. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Yura, Y. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Luo, J. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Kato, K. in: PubMed | Google Scholar |

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Ikeda, S. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Kawai, Y. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Hattori, T. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Okamoto, R. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Kizuki, M. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Miura-Yura, E. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Horitani, K. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Min, K. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Emoto, T. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Banno, H. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Takefuji, M. in: PubMed | Google Scholar

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Walsh, K. in: PubMed | Google Scholar |

1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Division of Vascular and Endovascular Surgery, Department of Surgery, Nagoya University Hospital, Nagoya, Japan

3Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

4Department of Medicine II, Kansai Medical Univeristy, Osaka, Japan

5Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Hyogo, Japan

6Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

7Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Researc, University of Virginia School of Medicine, Charlottesville, United States of America

Find articles by Murohara, T. in: PubMed | Google Scholar |

Published February 25, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI198708.
Copyright © 2026, Yonekawa et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 25, 2026 - Version history
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Abstract

Aortic aneurysms are age-linked aortic dilations that progress silently and carry high rupture mortality. 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 Tet2-deficient bone marrow into ApoE-knockout mice and induced aneurysms with angiotensin II. Tet2-clonal hematopoiesis mice developed significantly greater aortic dilation than controls. Interestingly, Tet2-deficient macrophages adopted an ACP5-positive, osteoclast-like state and produced more MMP9. Both genetic and pharmacological inhibition of osteoclast-like differentiation suppressed the Tet2-mediated aneurysmal growth in vivo. Thus, Tet2-driven clonal hematopoiesis accelerates aortic aneurysm progression through MMP9-producing osteoclast-like macrophages and therefore represents a tractable therapeutic axis.

Graphical Abstract
graphical abstract
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  • Version 1 (February 25, 2026): In-Press Preview
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