Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells.
Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells.
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DOI：
10.1186/s13073-023-01250-y
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发表时间：
2023-11-10
期刊：
影响因子：
12.3
通讯作者：
Diao, Yarui
中科院分区：
文献类型：
--
作者：
Southerland, Kevin W.;Xu, Yueyuan;Peters, Derek T.;Lin, Xin;Wei, Xiaolin;Xiang, Yu;Fei, Kaileen;Olivere, Lindsey A.;Morowitz, Jeremy M.;Otto, James;Dai, Qunsheng;Kontos, Christopher D.;Diao, Yarui
关键词：
慢性肢体威胁性缺血 (CLTI) 是外周动脉疾病 (PAD) 的一种严重表现，与约 15-20% 的 1 年肢体截肢率和大量死亡率相关。 CLTI 的一个关键特征是骨骼肌的再生能力受损；然而，造成这种损害的机制尚未完全清楚。在这项研究中，我们的目标是在细胞和转录组水平以及细胞间信号传导通路上描述与人体组织样本和 CLTI 小鼠模型中肢体缺血肌肉再生受损相关的病理变化。我们对同一 CLTI 患者和 CLTI 小鼠模型的缺血和非缺血肌肉进行了单细胞转录组分析。在这两个数据集中，我们分析了巨噬细胞和肌肉卫星细胞（MuSC）群体的基因表达变化以及差异细胞间信号相互作用和分化轨迹。 CLTI 患者骨骼肌的单细胞转录组分析和免疫荧光分析表明，缺血损伤的组织表现出促炎巨噬细胞特征。在小鼠 CLTI 模型中观察到了类似的结果。此外，对人类和小鼠数据集的综合分析表明，MuSC 的过早分化是缺血肢体肌肉再生失败的一个关键特征。此外，细胞间通讯的计算机推论和体外测定强调了巨噬细胞-MuSC 信号在缺血引起的肌肉损伤中的重要性。总的来说，我们的研究提供了第一个 CLTI 患者骨骼肌的单细胞转录组图谱和小鼠 CLTI 模型，强调了巨噬细胞和炎症通过与 MuSC 相互作用在调节 CLTI 肌肉再生中的关键作用。在线版本包含可在 10.1186/s13073-023-01250-y 获取的补充材料。
Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15–20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell–cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI. We performed single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients and from a murine model of CLTI. In both datasets, we analyzed gene expression changes in macrophage and muscle satellite cell (MuSC) populations as well as differential cell–cell signaling interactions and differentiation trajectories. Single-cell transcriptomic profiling and immunofluorescence analysis of CLTI patient skeletal muscle demonstrated that ischemic-damaged tissue displays a pro-inflammatory macrophage signature. Comparable results were observed in a murine CLTI model. Moreover, integrated analyses of both human and murine datasets revealed premature differentiation of MuSCs to be a key feature of failed muscle regeneration in the ischemic limb. Furthermore, in silico inferences of intercellular communication and in vitro assays highlight the importance of macrophage-MuSC signaling in ischemia induced muscle injuries. Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and a murine CLTI model, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs. The online version contains supplementary material available at 10.1186/s13073-023-01250-y.
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