Nonpreferential but Detrimental Accumulation of Macrophages With Clonal Hematopoiesis-Driver Mutations in Cardiovascular Tissues—Brief Report

Abstract

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an acquired genetic risk factor for both leukemia and cardiovascular disease. It results in proinflammatory myeloid cells in the bone marrow and blood; however, how these cells behave in the cardiovascular tissue remains unclear. Our study aimed at investigating whether CHIP-mutated macrophages accumulate preferentially in cardiovascular tissues and examining the transcriptome of tissue macrophages from DNMT3A or TET2 mutation carriers. METHODS: We recruited patients undergoing carotid endarterectomy or heart surgeries to screen for CHIP mutation carriers using targeted genomic sequencing. Myeloid and lymphoid cells were isolated from blood and cardiovascular tissue collected during surgeries using flow cytometry. DNA and RNA extracted from these sorted cells were subjected to variant allele frequency measurement using droplet digital polymerase chain reaction and transcriptomic profiling using bulk RNA sequencing, respectively. RESULTS: Using droplet digital polymerase chain reaction, we detected similar variant allele frequency of CHIP in monocytes from blood and macrophages from atheromas and heart tissues, even among CCR2+ (recruited) and CCR2− (resident) heart macrophages. Bulk RNA sequencing revealed a proinflammatory gene profile of myeloid cells from DNMT3A or TET2 mutation carriers compared with those from noncarriers. CONCLUSIONS: Quantitatively, CHIP-mutated myeloid cells did not preferentially accumulate in cardiovascular tissues, but qualitatively, they expressed a more disease-prone phenotype.

Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities

“…While monocytes give rise to CCR2+ macrophages, the CCR2-population harbors embryonically derived macrophages with divergent reports regarding the extent of substitution by monocyte-derived cells according to lineage tracing experiments in mice and analysis of sex-mismatched heart transplants or mutation variant allele frequencies in humans. [232][233][234][235] Differential gene expression profiles of CCR2+ and CCR2-cardiac macrophages share great similarities between mice and humans, supporting the translational value of the mouse model. Cardiac macrophages preserve tissue homeostasis through efferocytosis of cardiomyocyte exosomes containing damaged cell organelles, electrical coupling to cardiomyocytes, and defense against pathogens.…”