Hematopoietic loss of Y-chromosome in monocytes from heart failure patients associates with cardiac fibrosis signaling

Abstract Background Hematopoietic mosaic loss of Y chromosome (LOY) increases with age and associates with increased cardiovascular disease incidence. Furthermore, recent murine studies suggest that LOY could potentially promote cardiac fibrosis by stimulating the infiltration and activation of bone marrow-derived macrophages. Yet, specific signatures of hematopoietic LOY cells in patients with heart failure (HF) are missing. Methods and results To decode the genetic signature of circulating hematopoietic cells and assess the effects of LOY in human leukocytes, we performed single-cell RNA-sequencing (scRNA-seq) of immune cells from 10 male patients with chronic HF (mean age 67.3 years, ejection fraction 34.4%). We sorted immune cells by presence or absence of Y-chromosome-associated genes (figure 1A). Relative distribution of LOY was assessed, with monocytes having the greatest absolute count of LOY cells with no significant change in distribution among cell types. Given the abundance of monocytic LOY cells we investigated LOY monocytic cells transcriptional signatures (29810 Y-carrier monocytes, 2205 LOY monocytes) in an unbiased manner. Using a patient-specific, paired analysis, LOY monocytes showed significantly reduced expression of TGF-ß inhibiting genes (SMAD7, TGIF2) in LOY cells versus Y-carrier cells. Opposingly, from 193 upregulated genes, LOY cells showed elevated markers associated with monocyte/macrophage-mediated tissue damage and pro-fibrotic cardiac remodelling (S100A8, CLEC4D, TLR2). Gene ontology terms derived from upregulated genes in LOY cells further supported a mechanistic link to cardiac fibrosis by calling terms associated with TLR signaling, which are known to enhance cardiac fibrosis. (figure 1B). Conclusion This is the first study to decipher the genetic signature of LOY monocytes in HF patients. Our results considerably extend very recent experimental findings in mice that LOY sensitizes macrophages to enhanced profibrotic signaling. Diminished TGF-ß inhibitory molecules and enhanced TLR signaling may contribute to the aggravation of heart failure by LOY in patients with HF.HF mLOY scRNA-seq