Lin Yu-Ling, Yet Shaw-Fang, Hsu Yuan-Tong, Wang Guei-Jane, Hung Shih-Chieh
Institutes of Clinical Medicine, Pharmacology, and Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Stem Cell Laboratory, Department of Medical Research and Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, Republic of China; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Republic of China; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, Republic of China; Department of Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, Taiwan, Republic of China; Taiwan Bio Therapeutics, Taipei, Taiwan, Republic of China.
Institutes of Clinical Medicine, Pharmacology, and Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Stem Cell Laboratory, Department of Medical Research and Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, Republic of China; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Republic of China; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, Republic of China; Department of Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, Taiwan, Republic of China; Taiwan Bio Therapeutics, Taipei, Taiwan, Republic of China
Stem Cells Transl Med. 2015 Jan;4(1):44-55. doi: 10.5966/sctm.2014-0091. Epub 2014 Dec 10.
Transplantation of mesenchymal stem cells (MSCs) is beneficial in myocardial infarction and hind limb ischemia, but its ability to ameliorate atherosclerosis remains unknown. Here, the effects of MSCs on inhibiting endothelial dysfunction and atherosclerosis were investigated in human/mouse endothelial cells treated with oxidized low-density lipoprotein (oxLDL) and in apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet. Treatment with oxLDL inactivated the Akt/endothelial nitric-oxide synthase (eNOS) pathway, induced eNOS degradation, and inhibited nitric oxide (NO) production in endothelial cells. Coculture with human MSCs reversed the effects of oxLDL on endothelial cells and restored Akt/eNOS activity, eNOS level, and NO production. Reduction of endothelium-dependent relaxation and subsequent plaque formation were developed in apoE-/- mice fed a high-fat diet. Systemic infusion with mouse MSCs ameliorated endothelial dysfunction and plaque formation in high-fat diet-fed apoE-/- mice. Interestingly, treatment with interleukin-8 (IL8)/macrophage inflammatory protein-2 (MIP-2) alone induced the similar effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Neutralization antibodies (Abs) against IL8/MIP-2 also blocked the effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Consistently, MIP-2 injection alone induced the similar effect of MSCs on the endothelial function in high-fat diet-fed apoE-/- mice. The improvement in endothelial dysfunction by mouse MSCs was also blocked when pretreating MSCs with anti-MIP-2 Abs. In conclusion, MSC transplantation improved endothelial function and plaque formation in high-fat diet-fed apoE-/- mice. Activation of the Akt/eNOS pathway in endothelium by IL8/MIP-2 is involved in the protective effect of MSCs. The study helps support the use and clarify the mechanism of MSCs for ameliorating atherosclerosis.
间充质干细胞（MSCs）移植对心肌梗死和后肢缺血有益，但其改善动脉粥样硬化的能力尚不清楚。在此，研究了MSCs对经氧化低密度脂蛋白（oxLDL）处理的人/小鼠内皮细胞以及喂食高脂饮食的载脂蛋白E缺陷（apoE-/-）小鼠中抑制内皮功能障碍和动脉粥样硬化的作用。用oxLDL处理可使Akt/内皮型一氧化氮合酶（eNOS）途径失活，诱导eNOS降解，并抑制内皮细胞中一氧化氮（NO）的产生。与人MSCs共培养可逆转oxLDL对内皮细胞的影响，并恢复Akt/eNOS活性、eNOS水平和NO产生。喂食高脂饮食的apoE-/-小鼠出现内皮依赖性舒张功能降低及随后的斑块形成。向喂食高脂饮食的apoE-/-小鼠全身输注小鼠MSCs可改善内皮功能障碍和斑块形成。有趣的是，单独用白细胞介素-8（IL8）/巨噬细胞炎性蛋白-2（MIP-2）处理对经oxLDL处理的人/小鼠内皮细胞产生与人/小鼠MSCs类似的作用。针对IL8/MIP-2的中和抗体（Abs）也可阻断人/小鼠MSCs对经oxLDL处理的人/小鼠内皮细胞的作用。同样，单独注射MIP-2对喂食高脂饮食的apoE-/-小鼠的内皮功能产生与MSCs类似的作用。当用抗MIP-2 Abs预处理MSCs时，小鼠MSCs对内皮功能障碍的改善作用也被阻断。总之，MSCs移植改善了喂食高脂饮食的apoE-/-小鼠的内皮功能和斑块形成。IL8/MIP-2对内皮中Akt/eNOS途径的激活参与了MSCs的保护作用。该研究有助于支持MSCs在改善动脉粥样硬化方面的应用并阐明其机制。
