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Published on: May 26, 2021
Cell-intrinsic effects of clonal hematopoiesis in heart failure
Wesley T Abplanalp1,2,3, Bianca Schuhmacher1,3, Sebastian Cremer1,2,3
1Institute of Cardiovascular Regeneration, Goethe University, Frankfurt, Germany.
Insights
Clonal hematopoiesis (CHIP) involves mutations in blood stem cells, worsening heart failure outcomes. CHIP mutant immune cells, like monocytes and T cells, show increased inflammation and activation, amplifying disease progression.
Area of Science:
- Immunology
- Genetics
- Cardiology
Background:
- Clonal hematopoiesis of indeterminate potential (CHIP) arises from somatic mutations in hematopoietic stem cells.
- CHIP is linked to poorer prognoses in heart failure patients and is associated with heightened inflammation.
- The source of this inflammation—whether from mutant cells or systemic activation—remains unclear.
Purpose of the Study:
- To investigate the cell-intrinsic effects of CHIP mutant cells in heart failure patients.
- To determine how CHIP impacts immune cell function and inflammatory signaling.
Main Methods:
- Utilized an advanced single-cell sequencing pipeline, MutDetect-Seq.
- Analyzed gene expression profiles of monocytes, CD4+ T cells, and NK cells from heart failure patients with CHIP.
Main Results:
- DNMT3A mutant monocytes, CD4+ T cells, and NK cells displayed distinct altered gene expression profiles.
- Mutant monocytes showed increased inflammation and phagocytosis-related genes.
- Mutant T cells and NK cells exhibited heightened activation and effector functions.
- Paracrine signaling pathways between mutant and wild-type monocytes and T cells were identified, amplifying inflammatory circuits.
Conclusions:
- CHIP mutant immune cells possess intrinsic pro-inflammatory and activation signatures.
- These cellular changes and amplified inflammatory signaling contribute to the worse prognosis observed in heart failure patients with CHIP.
- Provides new understanding of CHIP's role in cardiovascular disease pathogenesis.
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.
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