Human Umbilical Cord-Derived Mesenchymal Stem Cell Therapy Ameliorates Nonalcoholic Fatty Liver Disease in Obese Type 2 Diabetic Mice
Human Umbilical Cord-Derived Mesenchymal Stem Cell Therapy Ameliorates Nonalcoholic Fatty Liver Disease in Obese Type 2 Diabetic Mice
复制标题
人脐带间充质干细胞疗法可改善肥胖 2 型糖尿病小鼠的非酒精性脂肪肝
DOI：
10.1155/2019/8628027
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发表时间：
2019-11-03
影响因子：
4.3
通讯作者：
Mu, Yiming
中科院分区：
文献类型：
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作者：
Li, Bing;Cheng, Yu;Mu, Yiming
非酒精性脂肪性肝病（NAFLD）在2型糖尿病（T2DM）患者中越来越常见。这两种情况可以协同作用，产生不良后果。然而，目前NAFLD和T2DM患者的治疗选择是有限的。人脐带源性间充质干细胞（UC-MSCs）已显示出治疗糖尿病和肝脏疾病（如肝硬化和暴发性肝衰竭）的潜力。本研究旨在探讨人UC-MSCs对以肥胖诱导的高血糖、血脂异常、肝脂肪变性和肝功能障碍为特征的NAFLD和T2DM小鼠模型的影响。30周龄雄性C57BL/ 6db /db小鼠，每周1次经尾静脉输注人UC-MSCs或磷酸盐缓冲盐水（PBS），连续6周。以年龄匹配的雄性C57BL/6野生型db/+小鼠为对照。每周测量体重和随机血糖。第六次输注1周后，行腹腔葡萄糖耐量试验和胰岛素耐量试验，取血、取肝进行生化和组织病理学检查。采用实时定量逆转录酶聚合酶链反应（qRT-PCR）、免疫荧光染色和western blot检测脂质代谢和调控途径相关基因的表达。UC-MSC输注可显著改善高血糖，降低肝转氨酶升高，降低脂质含量，包括甘油三酯、总胆固醇和低密度脂蛋白胆固醇。此外，肝组织病变明显减少，脂质积累减少，肝脂肪变性减轻。机制上，我们发现UC-MSCs通过增加脂肪酸氧化相关基因的表达和抑制脂肪生成相关基因的表达来调节脂质代谢，这些基因的表达与上调HNF4 α - ces2通路有关。我们的研究结果表明，人UC-MSCs可以改善db/db小鼠的NAFLD和逆转代谢综合征。因此，UC-MSCs可能成为T2DM合并NAFLD患者的一种新型治疗剂。
Nonalcoholic fatty liver disease (NAFLD) is increasingly common among patients with type 2 diabetes mellitus (T2DM). The two conditions can act synergistically to produce adverse outcomes. However, the therapeutic options for patients with NAFLD and T2DM are currently limited. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) have shown therapeutic potential for diabetes and hepatic disorders such as liver cirrhosis and fulminant hepatic failure. The present study is aimed at investigating the effect of human UC-MSCs on a mouse model of NAFLD and T2DM, characterized by obesity-induced hyperglycaemia, dyslipidaemia, hepatic steatosis, and liver dysfunction. Thirty-week-old male C57BL/6 db/db mice were infused with human UC-MSCs or phosphate-buffered saline (PBS) via the tail vein once a week for six weeks. Age-matched male C57BL/6 wild-type db/+ mice were used as controls. Body weight and random blood glucose were measured every week. One week after the sixth infusion, intraperitoneal glucose tolerance tests and insulin tolerance tests were performed and the blood and liver were harvested for biochemical and histopathological examinations. Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), immunofluorescence staining, and western blot were performed to monitor the expression of the lipid metabolism- and regulatory pathway-related genes. UC-MSC infusions significantly ameliorated hyperglycaemia, attenuated the elevation of hepatic transaminases, and decreased lipid contents, including triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Moreover, histological lesions in the liver diminished markedly, as evidenced by reduced lipid accumulation and attenuated hepatic steatosis. Mechanistically, UC-MSCs were found to regulate lipid metabolism by increasing the expression of fatty acid oxidation-related genes and inhibiting the expression of lipogenesis-related genes, which were associated with the upregulation of the HNF4 alpha-CES2 pathway. Our results demonstrate that human UC-MSCs can ameliorate NAFLD and reverse metabolic syndrome in db/db mice. Thus, UC-MSCs may serve as a novel therapeutic agent for T2DM patients with NAFLD.