Niche-Dependent Regulations of Metabolic Balance in High-Fat Diet-Induced Diabetic Mice by Mesenchymal Stromal Cells
Niche-Dependent Regulations of Metabolic Balance in High-Fat Diet-Induced Diabetic Mice by Mesenchymal Stromal Cells
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DOI：
10.2337/db14-1042
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发表时间：
2015-03-01
期刊：
影响因子：
7.7
通讯作者：
Ho, Jennifer H.
中科院分区：
文献类型：
--
作者：
Ji, Andrea Tung-Qian;Chang, Yun-Chuang;Ho, Jennifer H.
骨髓间充质干细胞（Mesenchymal stromal cells，MSCs）在维持体内葡萄糖稳态和代谢平衡方面具有巨大的潜力。在这里，我们证明，在小鼠连续喂食高脂饮食（HFD），发展非胰岛素依赖型糖尿病，两次全身MSC移植有效地改善葡萄糖耐量和血糖稳态，并通过靶向胰腺和胰岛素敏感的组织和器官通过位点特异性机制减轻体重。间充质干细胞通过直接分化为胰岛素产生细胞和通过减轻胰腺中白细胞介素1（IL-1）和肿瘤坏死因子-（TNF-α）的细胞毒性来支持胰岛生长。MSC在糖尿病动物肝脏和骨骼肌中的定位也得到增强，因此改善了葡萄糖耐量，尽管没有观察到长期植入。MSC防止HFD诱导的脂肪肝发展并恢复肝细胞中的糖原储存。MSC移植后骨骼肌中IL-1受体拮抗剂和Glut 4的表达增加导致更好的血糖稳态。有趣的是，全身MSC移植不改变脂肪细胞数量，但它减少了脂肪组织中HFD诱导的细胞浸润，并降低了血清脂肪因子水平，包括瘦素和TNF-α。总之，全身MSC移植改善HFD诱导的肥胖，并通过生态位依赖的多系统调节恢复代谢平衡。这些发现支持了MSC的系统移植以纠正代谢失衡。
Mesenchymal stromal cells (MSCs) have great potential to maintain glucose homeostasis and metabolic balance. Here, we demonstrate that in mice continuously fed with high-fat diet (HFD) that developed non-insulin-dependent diabetes, two episodes of systemic MSC transplantations effectively improve glucose tolerance and blood glucose homeostasis and reduce body weight through targeting pancreas and insulin-sensitive tissues and organs via site-specific mechanisms. MSCs support pancreatic islet growth by direct differentiation into insulin-producing cells and by mitigating the cytotoxicity of interleukin 1 (IL-1) and tumor necrosis factor- (TNF-) in the pancreas. Localization of MSCs in the liver and skeletal muscles in diabetic animals is also enhanced and therefore improves glucose tolerance, although long-term engraftment is not observed. MSCs prevent HFD-induced fatty liver development and restore glycogen storage in hepatocytes. Increased expression of IL-1 receptor antagonist and Glut4 in skeletal muscles after MSC transplantation results in better blood glucose homeostasis. Intriguingly, systemic MSC transplantation does not alter adipocyte number, but it decreases HFD-induced cell infiltration in adipose tissues and reduces serum levels of adipokines, including leptin and TNF-. Taken together, systemic MSC transplantation ameliorates HFD-induced obesity and restores metabolic balance through multisystemic regulations that are niche dependent. Such findings have supported systemic transplantation of MSCs to correct metabolic imbalance.