Department of Medicine/Division of Cardiovascular Medicine, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Clinical and Translational Research Center, Buffalo, New York, USA.
PLoS One. 2013 Aug 26;8(8):e73861. doi: 10.1371/journal.pone.0073861. eCollection 2013.
Hypercholesterolemia plays a critical role in atherosclerosis. CD34+ CD45dim Lineage- hematopoietic stem/progenitor cells (HSPCs) give rise to the inflammatory cells linked to atherosclerosis. In mice, high cholesterol levels mobilize HSPCs into the bloodstream, and promote their differentiation to granulocytes and monocytes. The objective of our study was to determine how cholesterol levels affect HSPC quantity in humans.
We performed a blinded, randomized hypothesis generating study in human subjects (n=12) treated sequentially with statins of differing potencies to vary lipid levels. CD34+ HSPC levels in blood were measured by flow cytometry. Hematopoietic colony forming assays confirmed the CD34+ population studied as HSPCs with multlineage differentiation potential. Mobilizing cytokine levels were measured by ELISA.
The quantity of HSPCs was 0.15 ± 0.1% of buffy coat leukocytes. We found a weak, positive correlation between CD34+ HSPCs and both total and LDL cholesterol levels (r(2)=0.096, p < 0.025). Additionally, we tested whether cholesterol modulates CD34+ HSPCs through direct effects or on the levels of mobilizing cytokines. LDL cholesterol increased cell surface expression of CXCR4, G-CSFR affecting HSPC migration, and CD47 mediating protection from phagocytosis by immune cells. LDL cholesterol also increased proliferation of CD34+ HSPCs (28 ± 5.7%, n=6, p < 0.03). Finally, the HSPC mobilizing cytokine G-CSF (r(2)=0.0683, p < 0.05), and its upstream regulator IL-17 (r(2)=0.0891, p < 0.05) both correlated positively with LDL cholesterol, while SDF-1 levels were not significantly affected.
Our findings support a model where LDL cholesterol levels positively correlate with CD34+ HSPC levels in humans through effects on the levels of G-CSF via IL-17 promoting mobilization of HSPCs, and by direct effects of LDL cholesterol on HSPC proliferation. The findings are provocative of further study to determine if HSPCs, like cholesterol levels, are linked to CVD events.
高胆固醇血症在动脉粥样硬化中起着关键作用。CD34+CD45dim 谱系-造血干细胞/祖细胞（HSPCs）产生与动脉粥样硬化相关的炎症细胞。在小鼠中，高胆固醇水平将 HSPCs 动员到血液中，并促进它们分化为粒细胞和单核细胞。我们研究的目的是确定胆固醇水平如何影响人类 HSPC 的数量。
我们在接受不同效力他汀类药物序贯治疗以改变血脂水平的人类受试者（n=12）中进行了一项盲法、随机假设生成研究。通过流式细胞术测量血液中 CD34+HSPC 水平。造血集落形成测定证实所研究的 CD34+群体为具有多谱系分化潜能的 HSPCs。通过 ELISA 测量动员细胞因子水平。
HSPC 数量为白细胞层白细胞的 0.15±0.1%。我们发现 CD34+HSPC 与总胆固醇和 LDL 胆固醇水平之间存在微弱的正相关（r2=0.096，p<0.025）。此外，我们还测试了胆固醇是否通过直接作用或动员细胞因子的水平来调节 CD34+HSPCs。LDL 胆固醇增加了 CXCR4、G-CSFR 的细胞表面表达，影响 HSPC 迁移，CD47 介导免疫细胞吞噬作用的保护。LDL 胆固醇还增加了 CD34+HSPCs 的增殖（28±5.7%，n=6，p<0.03）。最后，HSPC 动员细胞因子 G-CSF（r2=0.0683，p<0.05）及其上游调节剂 IL-17（r2=0.0891，p<0.05）均与 LDL 胆固醇呈正相关，而 SDF-1 水平则无显著影响。
我们的研究结果支持这样一种模式，即 LDL 胆固醇水平通过影响 G-CSF 水平，通过 IL-17 促进 HSPC 动员，以及 LDL 胆固醇对 HSPC 增殖的直接作用，与人类 CD34+HSPC 水平呈正相关。这些发现提示我们进一步研究 HSPC 是否与胆固醇水平一样与 CVD 事件有关。
