Identification of the crucial roles of BAXhigh NK cells in human derived mesenchymal stem cell therapy for chronic heart failure patients

Abstract

Mesenchymal stem cells (MSCs) have demonstrated significant potential in heart failure (HF) treatment, but the exact mechanisms are still not fully understood. This research utilized single-cell RNA sequencing to examine alterations in peripheral blood mononuclear cells from heart failure patients pre- and post-MSC therapy. Moreover, we utilized Mendelian randomization (MR) analysis to identify causal genes linked to HF. Specifically, through scRNA-seq, we observed a progressive increase in Natural Killer (NK) cells within peripheral blood mononuclear cells (PBMCs) following MSC treatment. Furthermore, MR analysis identified the differentially expressed gene (DEG) BAX as a potential target gene for HF. Notably, the expression of BAX was significantly downregulated after MSC treatment, suggesting its potential as a therapeutic response biomarker. Cell-cell communication analysis revealed that BAX^high NK cells displayed reduced cell-cell communication and increased apoptotic activity. Enrichment analysis indicated an association between BAX^high NK cells and the “coagulant” pathway. Taken together, our findings suggest that BAX may contribute to the pathogenesis of HF by promoting coagulation and apoptotic pathways. In contrast, MSCs appear to suppress BAX expression, thereby inhibiting these pathways. MSC treatment increases the proportion of NK cells and reduces BAX^high NK cells, ultimately improving NK cell function, and ameliorating HF.