Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease.
Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease.
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DOI：
10.1161/circresaha.123.323161
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发表时间：
2023-10-27
影响因子：
20.1
通讯作者：
Ryan, Terence E.
中科院分区：
文献类型：
--
作者：
Pass, Caroline G.;Palzkill, Victoria;Tan, Jianna;Kim, Kyoungrae;Thome, Trace;Yang, Qingping;Fazzone, Brian;Robinson, Scott T.;O'Malley, Kerri A.;Yue, Feng;Scali, Salvatore T.;Berceli, Scott A.;Ryan, Terence E.
下肢外周动脉疾病（PAD）是一种日益流行的疾病，有效的治疗方案有限。在这里，我们提供了PAD肢体肌肉的单核图谱，以促进更好地了解构成病变肢体肌肉的细胞组成和转录差异。我们从20例PAD患者和12例非PAD对照中获得腓肠肌标本。分离细胞核，进行单核rna测序。通过主成分分析、差异表达分析和已知标记基因的迭代聚类来表征核的组成。进行生物信息学分析以确定PAD和非PAD细胞核之间基因表达的差异，以及随后对细胞间信号网络的分析。肌肉标本的附加组织学分析伴随着单核rna测序图谱。单核rna测序分析显示，与非PAD患者相比，PAD患者纤维类型发生转变，I型（慢/氧化）肌核较少，II型（快/糖酵解）肌核较多，这一点通过肌肉标本的免疫染色得到证实。来自PAD的肌核显示了涉及应激反应、自噬、缺氧和萎缩的基因的全面上调。肌核亚聚类还确定了以代谢失调为特征的PAD肌肉特有的人群。PAD肌肉在肌肉干细胞、再生肌核和纤维脂肪祖细胞中也显示出独特的转录谱和增加的转录组多样性。细胞间通讯网络分析显示，纤维脂肪生成祖细胞是PAD肌肉的主要信号中枢，而血管生成和骨形态发生蛋白信号的缺乏可能导致PAD患者肢体功能不良。这一参考单核rna测序图谱提供了对PAD条件下细胞组成、转录特征和细胞间通讯途径改变的全面分析。
Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. We obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls. Nuclei were isolated and single-nuclei RNA-sequencing was performed. The composition of nuclei was characterized by iterative clustering via principal component analysis, differential expression analysis, and the use of known marker genes. Bioinformatics analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the single-nuclei RNA-sequencing atlas. Single-nuclei RNA-sequencing analysis indicated a fiber type shift with patients with PAD having fewer type I (slow/oxidative) and more type II (fast/glycolytic) myonuclei compared with non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also identified populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regenerating myonuclei, and fibro-adipogenic progenitor cells. Analysis of intercellular communication networks revealed fibro-adipogenic progenitors as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogenetic protein signaling which may contribute to poor limb function in PAD. This reference single-nuclei RNA-sequencing atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.
影响因子：
7
作者：
Wang, Dinghui;Liu, Bin;Xiong, Tianhua;Yu, Wenlong;Yang, Huiping;Wang, Jing;Jing, Xiaodong;She, Qiang
通讯作者：
She, Qiang
影响因子：
10.6
作者：
Ryan TE;Kim K;Scali ST;Berceli SA;Thome T;Salyers ZR;O'Malley KA;Green TD;Karnekar R;Fisher-Wellman KH;Yamaguchi DJ;McClung JM
通讯作者：
McClung JM