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Cited by 167Acute Myeloid Leukemia ResearchHematopoietic Stem Cell TransplantationCardiac Fibrosis and Remodeling

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

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Wang, Ying, Sano, Soichi, Yura, Yoshimitsu, Ke, Zhonghe, Sano, Miho, Oshima, Kosei, Ogawa, Hayato, Horitani, Keita +9 more·2020·JCI Insight
DOI 10.1172/jci.insight.135204PMC PMC7213793
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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.

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  • Alternatives via adoptive transfer of unfractionated BM cells into nonirradiated mice are limited by a fixed availability of BM niche space and restricted starting clonal fractions.

    “Although alternatives have been established via adoptive transfer of unfractionated BM cells into nonirradiated mice, these models are limited by a fixed availability of BM niche space and, thus, restricted starting clonal fractions.40,41”

    From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [40]

    The Results (p. 2) describe transfer of unfractionated bone marrow into nonirradiated mice and report low donor-cell engraftment compared with irradiated recipients. The Discussion (p. 8) likewise describes low but stable engraftment. These passages support limited donor contribution, but do not establish that fixed availability of bone marrow niche space causes restricted starting clonal fractions. (LLM, conf=0.82)

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Research works printed but not linked: 28

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Authors
Wang, Y., Sano, S., Yura, Y., Ke, Z., Sano, M., Oshima, K., Ogawa, H., Horitani, K., Min, K.-D., Miura-Yura, E., Kour, A., Evans, M. A., Zuriaga, M. A., Hirschi, K. K., Fuster, J. J., Pietras, E. M., & Walsh, K.
Affiliations
  • Army Medical University (CN)
  • University of Virginia (US)
  • University of Colorado Anschutz (US)
  • Boston University (US)
  • Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Corresponding author
Walsh, Kenneth
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2020-03-26
Volume
5
Issue
6
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.135204
PMC
PMC7213793
OpenAlex
W3011762292
Cited by
167
References
53
Citations by year
2026: 15 · 2025: 27 · 2024: 31 · 2023: 25 · 2022: 27 · 2021: 32 · 2020: 10
FWCI
14.84
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institutes of Health (HL131006,HL132564,HL138014, R01 DK119394)
  • American Heart Association (17POST33670076)
  • Ramón y Cajal program of the Spanish Ministerio de Ciencia, Innovación y Universidades (RYC-2016-20026)
  • Severo Ochoa Center of Excellence (SEV-2015-0505)
  • Kanae Foundation for the Promotion of Medical Science (404891)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
clonal hematopoiesis of indeterminate potential, TET2 mutation, age-related cardiac dysfunction, cardiac macrophages, cardiac hypertrophy, myocardial fibrosis, inflammation, hematopoietic stem and progenitor cells, healthspan, cardiovascular risk
MeSH terms
Clonal Hematopoiesis, Aging, Animals, Disease Models, Animal, DNA-Binding Proteins, Heart Diseases, Hematopoietic Stem Cells, Macrophages, Proto-Oncogene Proteins, Adoptive Transfer, Dioxygenases, Mice

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