Single-Cell RNA-Sequencing and Metabolomics Analyses Reveal the Contribution of Perivascular Adipose Tissue Stem Cells to Vascular Remodeling
Single-Cell RNA-Sequencing and Metabolomics Analyses Reveal the Contribution of Perivascular Adipose Tissue Stem Cells to Vascular Remodeling
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DOI：
10.1161/atvbaha.119.312732
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发表时间：
2019-10-01
影响因子：
8.7
通讯作者：
Xu, Qingbo
中科院分区：
文献类型：
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作者：
Gu, Wenduo;Nowak, Witold N.;Xu, Qingbo
目的：血管周围脂肪组织(PVAT)在维持血管内环境稳定中起着重要作用。然而，大多数研究将PVAT在血管重塑中的作用归因于血管周围脂肪细胞分泌的脂肪因子。PVAT中是否存在间充质干细胞并在血管再生中发挥作用尚不清楚。方法和结果：单细胞RNA测序可以高分辨率地直接显示PVAT来源的异质间充质干细胞(PV-ADSCs)，并显示两个不同的亚群，其中一个亚群具有对平滑肌分化至关重要的信号通路。对培养的PV-ADSCs进行伪时间分析，揭示其平滑肌分化的轨迹。将培养的PV-ADSCs移植到小鼠静脉移植模型中，提示PV-ADSCs可能通过平滑肌分化参与血管重塑。在机制上，转化生长因子-β1(转化生长因子-β1)和microRNA(MiR)-378a-3p模拟物的处理诱导了类似的PV-ADSCs代谢重编程，包括上调线粒体潜力和改变血脂水平，如增加胆固醇和促进平滑肌分化。结论：单细胞RNA测序可以在单细胞水平上直接显示PV-ADSC的异质性，并发现具有不同特征基因和信号通路的两个亚群。PVAT在血管再生中的作用部分归因于PV-ADSCs及其向平滑肌细胞的分化。机制研究表明miR-378a-3p是一种有效的代谢重编程调节剂，可作为血管再生的潜在治疗靶点。
Objective: Perivascular adipose tissue (PVAT) plays a vital role in maintaining vascular homeostasis. However, most studies ascribed the function of PVAT in vascular remodeling to adipokines secreted by the perivascular adipocytes. Whether mesenchymal stem cells exist in PVAT and play a role in vascular regeneration remain unknown. Approach and Results: Single-cell RNA-sequencing allowed direct visualization of the heterogeneous PVAT-derived mesenchymal stem cells (PV-ADSCs) at a high resolution and revealed 2 distinct subpopulations, among which one featured signaling pathways crucial for smooth muscle differentiation. Pseudotime analysis of cultured PV-ADSCs unraveled their smooth muscle differentiation trajectory. Transplantation of cultured PV-ADSCs in mouse vein graft model suggested the contribution of PV-ADSCs to vascular remodeling through smooth muscle differentiation. Mechanistically, treatment with TGF-beta 1 (transforming growth factor beta 1) and transfection of microRNA (miR)-378a-3p mimics induced a similar metabolic reprogramming of PV-ADSCs, including upregulated mitochondrial potential and altered lipid levels, such as increased cholesterol and promoted smooth muscle differentiation. Conclusions: Single-cell RNA-sequencing allows direct visualization of PV-ADSC heterogeneity at a single-cell level and uncovers 2 subpopulations with distinct signature genes and signaling pathways. The function of PVAT in vascular regeneration is partly attributed to PV-ADSCs and their differentiation towards smooth muscle lineage. Mechanistic study presents miR-378a-3p which is a potent regulator of metabolic reprogramming as a potential therapeutic target for vascular regeneration.