Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
Department of Advanced Cardiology, University of Tokyo, Tokyo, Japan.
Sci Immunol. 2024 May 24;9(95):eade3814. doi: 10.1126/sciimmunol.ade3814.
Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor-β (TGF-β) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-β signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of "stress memory."
心力衰竭（HF）患者常经历反复的急性失代偿，并出现慢性肾脏病和衰弱综合征等合并症。尽管这表明合并症之间存在病理相互作用，但它们之间的联系机制仍不清楚。在这里，我们发现造血干细胞（HSCs）的改变是复发性 HF 和相关合并症的关键驱动因素。来自经历 HF 的小鼠的骨髓移植导致受者小鼠自发的心脏功能障碍和纤维化，以及对肾脏和骨骼肌损伤的易感性增加。HF 增强了 HSCs 产生促炎巨噬细胞的能力。在 HF 小鼠中，全基因组染色质可及性分析和单细胞 RNA-seq 显示 HSCs 中的转化生长因子-β（TGF-β）信号受到抑制，这与骨髓中交感神经活性受抑制相对应。抑制 TGF-β信号的骨髓移植同样加剧了心脏功能障碍。总之，这些结果表明心脏应激调节 HSCs 的表观基因组，进而改变它们产生心脏巨噬细胞亚群的能力。这种 HSCs 的变化可能是反复发生 HF 事件和合并症的共同驱动因素，因为它是“应激记忆”的关键载体。
