Peripheral Ischemia Imprints Epigenetic Changes in Hematopoietic Stem Cells to Propagate Inflammation and Atherosclerosis.
Peripheral Ischemia Imprints Epigenetic Changes in Hematopoietic Stem Cells to Propagate Inflammation and Atherosclerosis.
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外周缺血会影响造血干细胞的表观遗传变化，从而传播炎症和动脉粥样硬化。
DOI：
10.1161/atvbaha.123.318956
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Dutta,Partha
中科院分区：
文献类型：
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作者：
Coppin,Emilie;Zhang,Xinyi;Ohayon,Lee;Johny,Ebin;Dasari,Ankush;Zheng,KangH;Stiekema,Lotte;Cifuentes-Pagano,Eugenia;Pagano,PatrickJ;Chaparala,Srilakshmi;Stroes,ErikS;Dutta,Partha
研究背景外周动脉疾病引起的外周缺血与全身炎症有关，炎症可加重动脉粥样硬化和心力衰竭等潜在并发症。然而，外周动脉疾病患者炎症和炎性细胞产生增加的机制尚不清楚。方法我们使用外周动脉疾病患者的外周血，用西方饮食喂养的ApoE−/−小鼠和标准实验室饮食的C57BL/6J小鼠进行后肢缺血(HI)。结果观察到外周动脉疾病患者和ApoE−/−小鼠血液中白细胞数量的增加。RNA测序和骨髓整体成像显示HSPC从成骨细胞壁龛迁移到血管壁龛，并过度增殖和分化。单细胞RNA测序显示，HI后炎症、髓系细胞动员和HSPC分化相关基因发生了变化。载脂蛋白E−/−小鼠HI后炎症加重加重动脉粥样硬化。令人惊讶的是，HI后，骨髓HSPC表达了更多的IL(IL)-1和IL-3受体。同时，I1r1和I3rb的启动子在HI后增加了H3K4me3和H3K27ac的标记。结论HI后HSPC炎症反应增加，骨髓血管壁内HSPC含量增加，IL-3Rb和IL-1R1(IL-1受体1)表达增加。此外，IL-3RB和IL-1R1信号在HSPC增殖、白细胞增多和动脉粥样硬化加重中起关键作用。
BackgroundPeripheral ischemia caused by peripheral artery disease is associated with systemic inflammation, which may aggravate underlying comorbidities such as atherosclerosis and heart failure. However, the mechanisms of increased inflammation and inflammatory cell production in patients with peripheral artery disease remain poorly understood.MethodsWe used peripheral blood collected from patients with peripheral artery disease and performed hind limb ischemia (HI) inApoe−/−mice fed a Western diet and C57BL/6J mice with a standard laboratory diet. Bulk and single-cell RNA sequencing analysis, whole-mount microscopy, and flow cytometry were performed to analyze hematopoietic stem and progenitor cell (HSPC) proliferation, differentiation, and relocation.ResultsWe observed augmented numbers of leukocytes in the blood of patients with peripheral artery disease andApoe−/−mice with HI. RNA sequencing and whole-mount imaging of the bone marrow revealed HSPC migration into the vascular niche from the osteoblastic niche and their exaggerated proliferation and differentiation. Single-cell RNA sequencing demonstrated alterations in the genes responsible for inflammation, myeloid cell mobilization, and HSPC differentiation after HI. Heightened inflammation inApoe−/−mice after HI aggravated atherosclerosis. Surprisingly, bone marrow HSPCs expressed higher amounts of the receptors for IL (interleukin)-1 and IL-3 after HI. Concomitantly, the promoters ofIl1r1andIl3rbhad augmented H3K4me3 and H3K27ac marks after HI. Genetic and pharmacological inhibition of these receptors resulted in suppressed HSPC proliferation, reduced leukocyte production, and ameliorated atherosclerosis.ConclusionsOur findings demonstrate increased inflammation, HSPC abundance in the vascular niches of the bone marrow, and elevated IL-3Rb and IL-1R1 (IL-1 receptor 1) expression in HSPC following HI. Furthermore, the IL-3Rb and IL-1R1 signaling plays a pivotal role in HSPC proliferation, leukocyte abundance, and atherosclerosis aggravation after HI.