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Cited by 76Cardiac Fibrosis and RemodelingAcute Myeloid Leukemia ResearchCongenital heart defects research

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

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Shumliakivska, Mariana, Luxán, Guillermo, Hemmerling, Inga, Scheller, Marina, Li, Xue, Müller-Tidow, Carsten, Schuhmacher, Bianca, Sun, Zhengwu +14 more·2024·Nature Communications
DOI 10.1038/s41467-023-43003-wPMC PMC10799021

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Abstract

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.

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  • hDNMT3A R882H monocyte-derived microglia expressed significant levels of Ccl5.

    “Notably, hDNMT3A R882H MoMg also expressed significant levels of Ccl5 , a chemokine that has been associated with brain pathologies and was shown to act on immune cells and neurons 53-55 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [55]

    The Results section on DNMT3A R882H mice reports Ccr2 expression in cardiac macrophage subclusters, not Ccl5 expression in monocyte-derived microglia. The Methods section on monocyte culture describes THP-1-derived macrophages. Searches for Ccl5 and microglia found no passage in our copy addressing the attributed finding; page numbers were unavailable. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Ccl5 encodes a chemokine that acts on immune cells and neurons and has been associated with brain pathologies, including PD.

    “Interestingly though, in particular the MoMg derived from hDNMT3A R882H HSC also prominently expressed Ccl5 , encoding a chemokine that acts on immune cells and neurons, and has been associated with brain pathologies, including PD 53-55 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [55]

    The Introduction and Results passages discuss DNMT3A-mutant monocytes, cardiac fibroblasts, and EGF signaling, not Ccl5’s effects on neurons or its association with brain pathologies. Searches for Ccl5, neurons, and Parkinson’s disease found no passage in our copy addressing the attributed claim. (LLM, conf=0.74)

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Authors
Shumliakivska, M., Luxán, G., Hemmerling, I., Scheller, M., Li, X., Müller-Tidow, C., Schuhmacher, B., Sun, Z., Dendorfer, A., Debes, A., Glaser, S.-F., Muhly-Reinholz, M., Kirschbaum, K., Hoffmann, J., Nagel, E., Puntmann, V. O., Cremer, S., Leuschner, F., Abplanalp, W. T., John, D., Zeiher, A. M., & Dimmeler, S.
Affiliations
  • Goethe University Frankfurt (DE)
  • Heidelberg University (DE)
  • Institut für Chirurgische Forschung (DE)
  • University Hospital Frankfurt (DE)
  • German Centre for Cardiovascular Research (DE)
Corresponding author
Dimmeler, Stefanie
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-01-19
Volume
15
Issue
1
Pages
606-606
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-43003-w
PMC
PMC10799021
OpenAlex
W4391034708
Cited by
76
References
5
Citations by year
2026: 23 · 2025: 36 · 2024: 12 · 2023: 4 · 2022: 1
FWCI
21.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
Funders
Deutsche Forschungsgemeinschaft (SFB 1366, SFB 1531)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
DNMT3A, clonal hematopoiesis of indeterminate potential, myocardial fibrosis, heart failure, cardiac fibroblasts, macrophages, paracrine signaling, HB-EGF, epigenetic regulators, antifibrotic therapy
MeSH terms
Clonal Hematopoiesis, DNA Methyltransferase 3A, DNA (Cytosine-5-)-Methyltransferases, Fibroblasts, Fibrosis, Heart Diseases, Heart Failure, Hematopoiesis, Humans, Leukocytes, Mononuclear, Mutation

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