Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis
Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis
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DOI：
10.1172/jci.insight.128528
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发表时间：
2019-06-06
期刊：
影响因子：
8
通讯作者：
Brown, Jonathan D.
中科院分区：
文献类型：
--
作者：
Guillermier, Christelle;Doherty, Sean P.;Brown, Jonathan D.
动脉粥样硬化斑块以白细胞和血管平滑肌细胞（VSMC）的局部增殖以及细胞代谢的变化为特征。然而，从技术上讲，不可能直接在体内动脉粥样硬化斑块细胞中研究葡萄糖利用与增殖之间的关系。我们使用多同位素成像质谱（MIMS），一种定量成像平台，测量动脉粥样硬化斑块中细胞分裂和葡萄糖利用的亚细胞器分辨率。在已建立的斑块中，同位素处理1周后，65%的内膜泡沫细胞和仅4%的中膜VSMCs被N-15-胸苷标记。分裂的细胞表现出增强的葡萄糖标记。MIMS在泡沫细胞内的多个亚细胞区室中检测到H-2-葡萄糖标记，包括脂滴、胞质和染色质。出乎意料的是，我们确定了一个强烈的焦点区域的H-2标记的VSMCs的斑块。这种信号在没有动脉粥样硬化的主动脉区域减弱。在晚期斑块中。泡沫细胞和VSMCs的N-15-胸苷和H-2-葡萄糖标记明显减少。这些数据表明VSMC葡萄糖代谢的显著异质性依赖于VSMC的增殖状态和与斑块的接近程度。此外，这些结果揭示了定量质谱结合同位素成像如何补充用于直接在体内生长的动脉粥样硬化斑块中研究细胞生物学的其他方法。
Atherosclerotic plaques feature local proliferation of leukocytes and vascular smooth muscle cells (VSMCs) and changes in cellular metabolism. Yet the relationship between glucose utilization and proliferation has been technically impossible to study directly in cells of atherosclerotic plaques in vivo. We used multi-isotope imaging mass spectrometry (MIMS), a quantitative imaging platform, to measure coincident cell division and glucose utilization at suborganelle resolution in atherosclerotic plaques. In established plaques, 65% of intimal foam cells and only 4% of medial VSMCs were labeled with N-15-thymidine after 1 week of isotope treatment. Dividing cells demonstrated heightened glucose labeling. MIMS detected H-2-glucose label in multiple subcellular compartments within foam cells, including lipid droplets, the cytosol, and chromatin. Unexpectedly, we identified an intensely focal region of H-2-label in VSMCs underlying plaques. This signal diminished in regions of aorta without atherosclerosis. In advanced plaques. N-15-thymidine and H-2-glucose labeling in foam cells and VSMCs significantly decreased. These data demonstrate marked heterogeneity in VSMC glucose metabolism that was dependent on both proliferative status and proximity of VSMCs to plaques. Furthermore, these results reveal how quantitative mass spectrometry coupled with isotope imaging can complement other methods used to study cell biology directly in the growing atherosclerotic plaque in vivo.