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

Shumliakivska, M.; Luxan, G.; Hemmerling, I.; Abplanalp, W. T.; Li, X.; Scheller, M.; Muller-Tidow, C.; Leuschner, F.; Schuhmacher, B.; Debes, A.; Glaser, S.-F.; Muhly Reinholz, M.; Kirschbaum, K.; Hoffmann, J.; Nagel, E.; Puntmann, V. O.; John, D.; Cremer, S.; Zeiher, A. M.; Dimmeler, S.

doi:10.1101/2023.01.07.521766

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bioRxiv · 10.1101/2023.01.07.521766

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

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Abstract

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and the cardiac tissue. We demonstrate that CHIP augments macrophage-to-cardiac fibroblasts interactions. Mechanistically, the secretome of DNMT3A-silenced monocytes leads to myofibroblast activation, partially through epidermal growth factor (EGFR) signaling. Harboring DNMT3A CHIP-driver mutations is associated with increased cardiac interstitial fibrosis in mice and patients, and, thereby, may contribute to the poor outcome. These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/521766v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@10a365aorg.highwire.dtl.DTLVardef@176807borg.highwire.dtl.DTLVardef@ed3f47org.highwire.dtl.DTLVardef@1d572b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Shumliakivska, M., Luxan, G., Hemmerling, I., Abplanalp, W. T., Li, X., Scheller, M., Muller-Tidow, C., Leuschner, F., Schuhmacher, B., Debes, A., Glaser, S.-F., Muhly Reinholz, M., Kirschbaum, K., Hoffmann, J., Nagel, E., Puntmann, V. O., John, D., Cremer, S., Zeiher, A. M., Dimmeler, S.. 2023-01-09. DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts. https://doi.org/10.1101/2023.01.07.521766

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