The single-cell transcriptomic dissection analysis: Platelet-t cell/macrophage crosstalk and immune imbalance in aplastic anemia (AA)

Abstract

Abstract Background the pathogenesis of HSPCs impairment in aplastic anemia (AA) remains unclear. In this study, in addition to focusing on CD8+ T cells, we also conducted an in-depth investigation into platelets, CD4+ T cells, macrophages, and mitochondrial energy metabolism, aiming to elucidate the cellular atlas changes associated with bone marrow failure (BMF). Methods we successfully constructed a BMF mouse model closest to the physiological and pathological process of AA patients, analyzed the single-cell landscape of immunological responses. Analysis of different immune cell interactions and identification of the key roles for T cells, macrophages, platelets, and mitochondria in BMF pathogenesis. Results platelets regulate CD4+/CD8+ T cells, and macrophages by releasing PF4. CXCR3/CXCR5 bind to PF4, activating mitochondrial signaling pathways. The decrease of Treg, weakening immunosuppression. Additionally, there is a significant increase in CD8+ effector T cells. Increased energy metabolism was observed in CD8+ stress T cells. It should be noted that, platelet reduction itself in AA weakens energy metabolism, subsequently impairing the hemostatic and thrombotic functions. However, platelets' regulatory function in immune cells remains significant. An imbalance in M1 and M2 macrophage polarization is observed. While a new phenotype of macrophages named “Msuntan” cell and CD8+ naive T cells are important cell phenotypes in marrow aging, not contribute to pathology failure. Conclusion the possible mechanisms of BMF in AA: based on PF4, platelet-T cell/macrophage crosstalk leads to immune overactivation and the release of cytokines such as IFN-γ and TNF-α, which attack the marrow. Therefore, transforming imbalanced CD8+ effector T cells, stress T cells, Treg cells, and M1/M2 macrophages into CD8+ naive T cells and Msuntan macrophages via inhibiting platelet immune regulatory function, may provide a promising strategy to reverse BMF. KEYWORDS Bone Marrow Failure (BMF), Aplastic Anemia (AA), Single-cell sequencing, Platelet, Immune cells