Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy.
Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy.
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单细胞重建进展轨迹揭示病理性心脏肥大的干预原则
DOI：
10.1161/circulationaha.119.043053
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发表时间：
2020-05-26
期刊：
影响因子：
37.8
通讯作者：
Wang, Li
中科院分区：
文献类型：
--
作者：
Ren, Zongna;Yu, Peng;Wang, Li
背景：压力超负荷所致的病理性心肌肥厚是心力衰竭的常见前身，心力衰竭仍是一种主要的心血管疾病，其发病率和死亡率在全球范围内呈上升趋势。目前的治疗方法通常包括在心力衰竭发作后部分缓解心脏的工作量。因此，更多针对发病机制、阶段和细胞类型的治疗策略需要在细胞和分子水平上对整个进展进行精细的剖析。方法：通过分析11,492个单细胞的转录本并根据其分子特征识别包括心肌细胞和非心肌细胞在内的主要细胞类型，在压力超负荷诱导的小鼠心肌肥厚进展的不同阶段，我们表征了细胞类型之间的时空相互作用，并测试了可能的药物治疗策略以延缓其在体内的进展。结果：我们阐明了包括心肌细胞、内皮细胞、成纤维细胞和巨噬细胞在内的所有主要心脏细胞类型的动力学，以及它们各自的亚型在疾病发展过程中的作用。细胞串扰分析显示在心功能恶化过程中特定的非心肌细胞的阶段性利用。具体地说，巨噬细胞激活和亚型转换是心肌肥厚中期的关键事件，在心力衰竭患者的临床试验中，成功地被糖钠共转运体2抑制剂达帕利福秦以及两种心脏疾病新的抗炎药TD139和Argrain靶向，以保护心功能和减轻纤维化。在肥厚型心肌病和心力衰竭患者中也观察到了类似的肥大分子模式。结论：我们的研究不仅阐明了病理性心肌肥厚过程中细胞类型的动态变化串扰，而且为心脏疾病的细胞类型和阶段特异性干预策略提供了线索。
BACKGROUND: Pressure overload-induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart's workload after the onset of heart failure. Thus, more pathogenesis-, stage-, and cell type-specific treatment strategies require refined dissection of the entire progression at the cellular and molecular levels.METHODS: By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and noncardiomyocytes, on the basis of their molecular signatures, at different stages during the progression of pressure overload-induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay among cell types, and tested potential pharmacological treatment strategies to retard its progression in vivo.RESULTS: We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific noncardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose cotransporter 2 inhibitor, in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure.CONCLUSIONS: Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.