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.”

中文翻译：

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心力衰竭通过先天免疫记忆促进多种疾病


心力衰竭（HF）患者经常会出现反复的急性失代偿，并出现慢性肾病和虚弱综合征等合并症。尽管这表明合并症之间存在病理相互作用，但人们对将它们联系起来的机制知之甚少。在这里，我们发现造血干细胞 (HSC) 的改变是心力衰竭复发和相关合并症的关键驱动因素。来自经历过心力衰竭的小鼠的骨髓移植导致受体小鼠自发性心脏功能障碍和纤维化，并增加了对肾脏和骨骼肌损伤的脆弱性。 HF 增强了 HSC 产生促炎巨噬细胞的能力。在 HF 小鼠中，整体染色质可及性分析和单细胞 RNA 测序表明，HSC 中的转化生长因子-β (TGF-β) 信号传导受到抑制，这与骨髓中交感神经活动的抑制相对应。 TGF-β信号传导受到抑制的小鼠骨髓移植同样会加剧心脏功能障碍。总的来说，这些结果表明心脏应激调节 HSC 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。 HSC 的这种变化可能是反复发生心力衰竭事件和合并症的常见驱动因素，因为它是“压力记忆”的关键载体。