Skin-Derived Mesenchymal Stem Cells Alleviate Atherosclerosis via Modulating Macrophage Function
Skin-Derived Mesenchymal Stem Cells Alleviate Atherosclerosis via Modulating Macrophage Function
复制标题
皮肤源性间充质干细胞通过调节巨噬细胞功能减轻动脉粥样硬化。
DOI：
10.5966/sctm.2015-0020
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发表时间：
2015-11-01
影响因子：
6
通讯作者：
Gao, Pingjin
中科院分区：
文献类型：
--
作者：
Li, Qun;Sun, Weihong;Gao, Pingjin
骨髓间充质干细胞（MSCs）具有免疫抑制作用，能显著抑制载脂蛋白E基因敲除（apoE（-/-））小鼠动脉粥样硬化（AS）斑块的形成。值得注意的是，最大的淋巴器官，皮肤，提供了一个容易获得的和理想的组织来源的MSC的分离：皮肤来源的MSC（S-MSC）。然而，S-MSCs治疗AS的作用和机制尚不清楚。因此，我们研究了S-MSC治疗对apoE（-/-）小鼠动脉粥样硬化斑块形成的直接影响。将50只apoE（-/-）小鼠分为4组：对照组（AS）、S-MSC处理组（S-MSC处理）、核因子-κ B（NF-κ B）（-/-）-S-MSC处理组（KO-S-MSC处理）和额外的S-MSC迁移组。头臂动脉超声生物显微镜（UBM）分析显示，与对照组相比，S-MSC治疗显著减小了病变大小（p <0.01）。组织学研究表明，小鼠主动脉弓的斑块面积显着减少后，S-MSC治疗。所有改变均依赖于NF-κ B活化。尾静脉注射后，S-MSCs能够迁移到动脉粥样硬化斑块，并选择性地在巨噬细胞附近定居。S-MSC治疗减少了促炎细胞因子肿瘤坏死因子（TNF）-α的释放，增加了动脉粥样硬化斑块中抗炎因子白细胞介素（IL）-10的表达，这也依赖于NF-κ B活化。在体外实验中，我们发现脂多糖（LPS）诱导S-MSCs表达NF-κ B依赖的环氧合酶-2（考克斯-2）。LPS刺激的S-MSCs与巨噬细胞共培养后，前列腺素E2（PGE 2）表达明显增加。当与S-MSC一起培养时，LPS刺激的巨噬细胞产生较少的TNF-α/IL-1 β和较多的IL-10，尽管两者都依赖于NF-κ B，但如果用考克斯-2抑制剂或EP 2/EP 4拮抗剂预处理S-MSC，则IL-10的释放减少。我们的数据表明，S-MSCs通过调节巨噬细胞的功能来抑制apoE（-/-）小鼠动脉粥样硬化斑块的形成，这表明S-MSCs可能在基于干细胞的AS治疗中发挥作用。
Mesenchymal stem cells (MSCs) exhibit immunosuppressive efficacy and significantly inhibit the formation of the atherosclerosis (AS) plaque in apolipoprotein E-knockout (apoE(-/-)) mice. Of note, the largest lymphoid organ, the skin, provides a readily accessible and ideal source of tissue for the isolation of MSCs: skin-derived MSCs (S-MSCs). However, the effect and the mechanism of the therapeutic properties of S-MSCs in the progression of AS are unclear. We therefore investigated a direct effect of S-MSC treatment in the formation of atherosclerotic plaque in apoE(-/-) mice. Fifty apoE(-/-) mice were divided into four groups: the control group (AS), the S-MSC treatment group (S-MSC treatment), the nuclear factor-kappa B (NF-kappa B)(-/-)-S-MSC treatment group (KO-S-MSC treatment), and the additional S-MSC migration group. Brachiocephalic artery ultrasound biomicroscope (UBM) analysis showed that S-MSC treatment significantly reduced lesion size compared with the control groups (p < .01). Histological studies demonstrated that the plaque area of the mouse aortic arch was significantly decreased after S-MSC treatment. All alterations were dependent on NF-kappa B activation. After tail-vein injection, S-MSCs were capable of migrating to atherosclerotic plaque and selectively taking up residence near macrophages. S-MSC treatment reduced the release of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and increased the expression of the anti-inflammatory factor interleukin (IL)-10 in the atherosclerotic plaque, which was also dependent on NF-kappa B activation. In vitro, we found lipopolysaccharide (LPS) induced NF-kappa B-dependent expression of cyclooxygenase-2 (COX-2) in S-MSCs. Prostaglandin E2 (PGE2) expression was markedly increased after LPS-stimulated S-MSCs were cocultured with macrophages. LPS-stimulated macrophages produced less TNF-alpha/IL-1 beta and more IL-10 when cultured with S-MSCs, and although both were dependent upon NF-kappa B, the release of IL-10 was diminished if the S-MSCs were pretreated with a COX-2 inhibitor or an EP2/EP4 antagonist. Our data demonstrated that S-MSCs inhibited the formation of the atherosclerotic plaque in apoE(-/-) mice by modulating the functionality of macrophages, suggesting that S-MSCs may potentially have a role in stem cellbased therapy for AS.