Cell-intrinsic effects of clonal hematopoiesis in heart failure

Nat Cardiovasc Res. 2023 Sep;2(9):819-834. doi: 10.1038/s44161-023-00322-x. Epub 2023 Sep 4.

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is caused by somatic mutations in hematopoietic stem cells and associates with worse prognosis in patients with heart failure. Patients harboring CHIP mutations show enhanced inflammation. However, whether these signatures are derived from the relatively low number of cells harboring mutations or are indicators of systemic pro-inflammatory activation that is associated with CHIP is unclear. Here we assess the cell-intrinsic effects of CHIP mutant cells in patients with heart failure. Using an improved single-cell sequencing pipeline (MutDetect-Seq), we show that DNMT3A mutant monocytes, CD4+ T cells and NK cells exhibit altered gene expression profiles. While monocytes showed increased genes associated with inflammation and phagocytosis, T cells and NK cells present increased activation signatures and effector functions. Increased paracrine signaling pathways are predicted and validated between mutant and wild-type monocytes and T cells, which amplify inflammatory circuits. Altogether, these data provide novel insights into how CHIP might promote a worse prognosis in patients with heart failure.

MeSH terms

  • Aged
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / metabolism
  • Clonal Hematopoiesis* / genetics
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methyltransferase 3A*
  • Female
  • Heart Failure* / genetics
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Killer Cells, Natural / immunology
  • Male
  • Middle Aged
  • Monocytes* / metabolism
  • Mutation*
  • Paracrine Communication
  • Phagocytosis / genetics
  • Phenotype
  • Single-Cell Analysis
  • Transcriptome

Substances

  • DNMT3A protein, human
  • DNA Methyltransferase 3A
  • DNA (Cytosine-5-)-Methyltransferases