IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-023-43003-w.html
   My bibliography  Save this article

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

Author

Listed:
  • Mariana Shumliakivska

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt
    German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    Cardiopulmonary Institute (CPI))

  • Guillermo Luxán

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt
    German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    Cardiopulmonary Institute (CPI))

  • Inga Hemmerling

    (University Hospital Heidelberg, University of Heidelberg
    German Center of Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim)

  • Marina Scheller

    (University of Heidelberg)

  • Xue Li

    (University Hospital Heidelberg, University of Heidelberg
    German Center of Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim)

  • Carsten Müller-Tidow

    (University of Heidelberg)

  • Bianca Schuhmacher

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt)

  • Zhengwu Sun

    (Walter-Brendel-Centre of Experimental Medicine, Hospital of the Ludwig-Maximilians-University Munich)

  • Andreas Dendorfer

    (Walter-Brendel-Centre of Experimental Medicine, Hospital of the Ludwig-Maximilians-University Munich)

  • Alisa Debes

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt)

  • Simone-Franziska Glaser

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt
    German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    Cardiopulmonary Institute (CPI))

  • Marion Muhly-Reinholz

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt)

  • Klara Kirschbaum

    (University Hospital Frankfurt)

  • Jedrzej Hoffmann

    (German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    University Hospital Frankfurt)

  • Eike Nagel

    (German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    University Hospital Frankfurt)

  • Valentina O. Puntmann

    (German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    University Hospital Frankfurt)

  • Sebastian Cremer

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt
    German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    Cardiopulmonary Institute (CPI)
    University Hospital Frankfurt)

  • Florian Leuschner

    (University Hospital Heidelberg, University of Heidelberg
    German Center of Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim)

  • Wesley Tyler Abplanalp

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt
    German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    Cardiopulmonary Institute (CPI))

  • David John

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt
    Cardiopulmonary Institute (CPI))

  • Andreas M. Zeiher

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt
    German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    Cardiopulmonary Institute (CPI))

  • Stefanie Dimmeler

    (Institute for Cardiovascular Regeneration, Goethe University Frankfurt
    German Center of Cardiovascular Research (DZHK), Partner Site Rhine/Main
    Cardiopulmonary Institute (CPI))

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.

Suggested Citation

  • Mariana Shumliakivska & Guillermo Luxán & Inga Hemmerling & Marina Scheller & Xue Li & Carsten Müller-Tidow & Bianca Schuhmacher & Zhengwu Sun & Andreas Dendorfer & Alisa Debes & Simone-Franziska Glas, 2024. "DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-43003-w
    DOI: 10.1038/s41467-023-43003-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-43003-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-43003-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Andrea Ventura & David G. Kirsch & Margaret E. McLaughlin & David A. Tuveson & Jan Grimm & Laura Lintault & Jamie Newman & Elizabeth E. Reczek & Ralph Weissleder & Tyler Jacks, 2007. "Restoration of p53 function leads to tumour regression in vivo," Nature, Nature, vol. 445(7128), pages 661-665, February.
    2. Margarete A. Fabre & José Guilherme Almeida & Edoardo Fiorillo & Emily Mitchell & Aristi Damaskou & Justyna Rak & Valeria Orrù & Michele Marongiu & Michael Spencer Chapman & M. S. Vijayabaskar & Joann, 2022. "The longitudinal dynamics and natural history of clonal haematopoiesis," Nature, Nature, vol. 606(7913), pages 335-342, June.
    3. Carola Fischer & Hendrik Milting & Evelyn Fein & Elisabeth Reiser & Kun Lu & Thomas Seidel & Camilla Schinner & Thomas Schwarzmayr & Rene Schramm & Roland Tomasi & Britta Husse & Xiaochun Cao-Ehlker &, 2019. "Long-term functional and structural preservation of precision-cut human myocardium under continuous electromechanical stimulation in vitro," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    4. Suoqin Jin & Christian F. Guerrero-Juarez & Lihua Zhang & Ivan Chang & Raul Ramos & Chen-Hsiang Kuan & Peggy Myung & Maksim V. Plikus & Qing Nie, 2021. "Inference and analysis of cell-cell communication using CellChat," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yanchuan Li & Huamei Li & Cheng Peng & Ge Meng & Yijun Lu & Honglin Liu & Li Cui & Huan Zhou & Zhu Xu & Lingyun Sun & Lihong Liu & Qing Xiong & Beicheng Sun & Shiping Jiao, 2024. "Unraveling the spatial organization and development of human thymocytes through integration of spatial transcriptomics and single-cell multi-omics profiling," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    2. Tim Flerlage & Jeremy Chase Crawford & E. Kaitlynn Allen & Danielle Severns & Shaoyuan Tan & Sherri Surman & Granger Ridout & Tanya Novak & Adrienne Randolph & Alina N. West & Paul G. Thomas, 2023. "Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Shirong Cao & Yu Pan & Andrew S. Terker & Juan Pablo Arroyo Ornelas & Yinqiu Wang & Jiaqi Tang & Aolei Niu & Sarah Abu Kar & Mengdi Jiang & Wentian Luo & Xinyu Dong & Xiaofeng Fan & Suwan Wang & Matth, 2023. "Epidermal growth factor receptor activation is essential for kidney fibrosis development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Kristoffer Sølvsten Burgdorf & Niels Grarup & Johanne Marie Justesen & Marie Neergaard Harder & Daniel Rinse Witte & Torben Jørgensen & Annelli Sandbæk & Torsten Lauritzen & Sten Madsbad & Torben Hans, 2011. "Studies of the Association of Arg72Pro of Tumor Suppressor Protein p53 with Type 2 Diabetes in a Combined Analysis of 55,521 Europeans," PLOS ONE, Public Library of Science, vol. 6(1), pages 1-6, January.
    5. Christopher Bono & Yang Liu & Alexander Ferrena & Aneesa Valentine & Deyou Zheng & Bernice E. Morrow, 2023. "Single-cell transcriptomics uncovers a non-autonomous Tbx1-dependent genetic program controlling cardiac neural crest cell development," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Lichun Ma & Sophia Heinrich & Limin Wang & Friederike L. Keggenhoff & Subreen Khatib & Marshonna Forgues & Michael Kelly & Stephen M. Hewitt & Areeba Saif & Jonathan M. Hernandez & Donna Mabry & Roman, 2022. "Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Qingnan Liang & Yuefan Huang & Shan He & Ken Chen, 2023. "Pathway centric analysis for single-cell RNA-seq and spatial transcriptomics data with GSDensity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Faith H. Brennan & Yang Li & Cankun Wang & Anjun Ma & Qi Guo & Yi Li & Nicole Pukos & Warren A. Campbell & Kristina G. Witcher & Zhen Guan & Kristina A. Kigerl & Jodie C. E. Hall & Jonathan P. Godbout, 2022. "Microglia coordinate cellular interactions during spinal cord repair in mice," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    9. Sandra Curras-Alonso & Juliette Soulier & Thomas Defard & Christian Weber & Sophie Heinrich & Hugo Laporte & Sophie Leboucher & Sonia Lameiras & Marie Dutreix & Vincent Favaudon & Florian Massip & Tho, 2023. "An interactive murine single-cell atlas of the lung responses to radiation injury," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Ilmatar Rooda & Jasmin Hassan & Jie Hao & Magdalena Wagner & Elisabeth Moussaud-Lamodière & Kersti Jääger & Marjut Otala & Katri Knuus & Cecilia Lindskog & Kiriaki Papaikonomou & Sebastian Gidlöf & Ce, 2024. "In-depth analysis of transcriptomes in ovarian cortical follicles from children and adults reveals interfollicular heterogeneity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    11. Moujtaba Y. Kasmani & Paytsar Topchyan & Ashley K. Brown & Ryan J. Brown & Xiaopeng Wu & Yao Chen & Achia Khatun & Donia Alson & Yue Wu & Robert Burns & Chien-Wei Lin & Matthew R. Kudek & Jie Sun & We, 2023. "A spatial sequencing atlas of age-induced changes in the lung during influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    12. Wei Yang & Li-Bo Liu & Feng-Liang Liu & Yan-Hua Wu & Zi-Da Zhen & Dong-Ying Fan & Zi-Yang Sheng & Zheng-Ran Song & Jia-Tong Chang & Yong-Tang Zheng & Jing An & Pei-Gang Wang, 2023. "Single-cell RNA sequencing reveals the fragility of male spermatogenic cells to Zika virus-induced complement activation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    13. Luke Simpson & Andrew Strange & Doris Klisch & Sophie Kraunsoe & Takuya Azami & Daniel Goszczynski & Triet Minh & Benjamin Planells & Nadine Holmes & Fei Sang & Sonal Henson & Matthew Loose & Jennifer, 2024. "A single-cell atlas of pig gastrulation as a resource for comparative embryology," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    14. Erick Armingol & Hratch M. Baghdassarian & Cameron Martino & Araceli Perez-Lopez & Caitlin Aamodt & Rob Knight & Nathan E. Lewis, 2022. "Context-aware deconvolution of cell–cell communication with Tensor-cell2cell," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    15. Baptiste Lamarthée & Jasper Callemeyn & Yannick Van Herck & Asier Antoranz & Dany Anglicheau & Patrick Boada & Jan Ulrich Becker & Tim Debyser & Frederik De Smet & Katrien De Vusser & Maëva Eloudzeri , 2023. "Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    16. Xiaojian Lu & Yanwei Luo & Xichen Nie & Bailing Zhang & Xiaoyan Wang & Ran Li & Guangmin Liu & Qianyin Zhou & Zhizhong Liu & Liqing Fan & James M. Hotaling & Zhe Zhang & Hao Bo & Jingtao Guo, 2023. "Single-cell multi-omics analysis of human testicular germ cell tumor reveals its molecular features and microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    17. Tingting Liu & Zhenzhen Wang & Xiaotong Xue & Zhe Wang & Yuan Zhang & Zihao Mi & Qing Zhao & Lele Sun & Chuan Wang & Peidian Shi & Gongqi Yu & Meng Wang & Yonghu Sun & Fuzhong Xue & Hong Liu & Furen Z, 2024. "Single-cell transcriptomics analysis of bullous pemphigoid unveils immune-stromal crosstalk in type 2 inflammatory disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    18. Jingtao Wang & Gregory J. Fonseca & Jun Ding, 2024. "scSemiProfiler: Advancing large-scale single-cell studies through semi-profiling with deep generative models and active learning," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    19. Inmaculada Ruz-Maldonado & John T. Gonzalez & Hanming Zhang & Jonathan Sun & Alicia Bort & Inamul Kabir & Richard G. Kibbey & Yajaira Suárez & Daniel M. Greif & Carlos Fernández-Hernando, 2024. "Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    20. Anjun Ma & Xiaoying Wang & Jingxian Li & Cankun Wang & Tong Xiao & Yuntao Liu & Hao Cheng & Juexin Wang & Yang Li & Yuzhou Chang & Jinpu Li & Duolin Wang & Yuexu Jiang & Li Su & Gang Xin & Shaopeng Gu, 2023. "Single-cell biological network inference using a heterogeneous graph transformer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-43003-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.