Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan.
Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University School of Medicine, Nara, Japan.
Stem Cells Dev. 2020 Apr 15;29(8):488-497. doi: 10.1089/scd.2019.0250. Epub 2020 Mar 19.
Previous studies indicate that the administration of adipose tissue-derived stem cells (ADSCs) through the venous route improves insulin resistance partly through a reduction in the proinflammatory cytokines in diabetic animals. However, the effects of ADSC sheet transplantation for the treatment of diabetes and obesity still remained unknown. In this study, we investigated the effects of ADSC sheet transplantation into the subcutaneous sites on the diabetic state of mice fed high-fat and high-sucrose diet (HF/HSD). ADSCs were isolated and propagated from subcutaneous adipose tissues of non-diabetic intact mice. We used the thermoresponsive designated cell culture dishes to fabricate ADSC cell sheets. ADSC sheet transplantation into the subcutaneous sites significantly improved glucose intolerance induced by HF/HSD in mice. ADSC-conditioned medium (CM) augmented the phosphorylation of Akt with or without insulin in mouse C2C12 myotubes and mouse 3T3-L1 adipocytes. Plasma adiponectin and tumor necrosis factor-α (TNF-α) levels were significantly increased and decreased by ADSC sheet transplantation in mice with or without HF/HSD, respectively. Moreover, ADSC sheet enhanced adiponectin expression in the subcutaneous adipose tissues in HF/HSD-fed mice, whereas it reduced TNF-α expression in the visceral adipose tissues. ADSC-CM enhanced and reduced the protein levels of adiponectin and TNF-α in 3T3-L1 adipocytes, respectively. In conclusion, we first revealed that ADSC sheet transplantation into the subcutaneous sites improves glucose intolerance in mice fed with HF/HSD. Changes of adiponectin and TNF-α production from the host adipose tissues might be involved in the effects of ADSC sheet on glucose metabolism in mice. ADSC sheet transplantation therapy may be a novel clinical application for diabetes.
先前的研究表明，通过静脉途径给予脂肪组织源性干细胞（ADSCs）可部分通过降低糖尿病动物中的促炎细胞因子来改善胰岛素抵抗。然而，ADSC 片移植治疗糖尿病和肥胖的效果仍不清楚。在这项研究中，我们研究了将 ADSC 片移植到皮下部位对高脂肪和高蔗糖饮食（HF/HSD）喂养的糖尿病小鼠的糖尿病状态的影响。ADSCs 是从非糖尿病完整小鼠的皮下脂肪组织中分离和扩增的。我们使用热响应性指定细胞培养皿来制造 ADSC 细胞片。ADSC 片移植到皮下部位可显著改善 HF/HSD 诱导的小鼠葡萄糖耐量受损。ADSC 条件培养基（CM）在存在或不存在胰岛素的情况下均可增强 Akt 在 C2C12 肌管和 3T3-L1 脂肪细胞中的磷酸化。ADSC 片移植可分别增加和减少 HF/HSD 小鼠的血浆脂联素和肿瘤坏死因子-α（TNF-α）水平。此外，ADSC 片可增强 HF/HSD 喂养小鼠皮下脂肪组织中脂联素的表达，而减少内脏脂肪组织中 TNF-α的表达。ADSC-CM 可分别增强和减少 3T3-L1 脂肪细胞中脂联素和 TNF-α的蛋白水平。总之，我们首次揭示了将 ADSC 片移植到皮下部位可改善 HF/HSD 喂养的小鼠的葡萄糖耐量。宿主脂肪组织中脂联素和 TNF-α产生的变化可能参与了 ADSC 片对小鼠葡萄糖代谢的影响。ADSC 片移植治疗可能是糖尿病的一种新的临床应用。
