Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Institute of Basic Medical Sciences and School of Basic Medicine, Beijing, PR China.
Stem Cells Dev. 2011 Feb;20(2):259-67. doi: 10.1089/scd.2010.0072. Epub 2010 Oct 7.
A better understanding of the molecular mechanisms underlying the differentiation of human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) could provide new insights into the pathogenesis of a number of diseases, such as obesity and diabetes, and broaden the spectrum of potential hAD-MSCs-based cell therapy. In this study, we reported that a human microRNA, hsa-miR-138, could inhibit the adipogenic differentiation of hAD-MSCs. Our results showed that miR-138 was significantly down-regulated during adipogenic differentiation. Overexpression of miR-138 in hAD-MSCs could effectively reduce lipid droplets accumulation, inhibit expression of key adipogenic transcription factors cytidine-cytidine-adenosine-adenosine-thymidine (CCAAT) enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma 2 as well as several other adipogenic marker genes, such as fatty acid binding protein 4 and lipoprotein lipase. Further studies showed that the expression of adenovirus early region 1-A-like inhibitor of differentiation 1 (EID-1), a nuclear receptor coregulator, was inversely correlated with that of miR-138 when hAD-MSCs were differentiated into adipocytes. Knockdown of EID-1 by RNA interference inhibited adipocyte differentiation of hAD-MSCs. In addition, luciferase reporter assays demonstrated that miR-138 directly targeted the 3' untranslated region of EID-1, implying that the negative role of miR-138 in the adipocyte differentiation of hAD-MSCs is at least partially mediated via repressing EID-1. Taken together, this study shows that miR-138 plays a negative role in adipogenic differentiation and sheds light on the role of miRNAs during differentiation of hAD-MSCs toward adipocytes.
更好地理解人类脂肪组织来源间充质干细胞（hAD-MSCs）分化的分子机制，可以为许多疾病（如肥胖症和糖尿病）的发病机制提供新的见解，并拓宽潜在 hAD-MSCs 基于细胞治疗的范围。在这项研究中，我们报道了一种人类 microRNA，hsa-miR-138，可以抑制 hAD-MSCs 的成脂分化。我们的结果表明，miR-138 在成脂分化过程中显著下调。在 hAD-MSCs 中过表达 miR-138 可以有效减少脂滴积累，抑制关键成脂转录因子胞嘧啶-胞嘧啶-腺苷-腺苷-胸腺嘧啶（CCAAT）增强子结合蛋白α和过氧化物酶体增殖物激活受体γ 2 以及其他几种成脂标记基因的表达，如脂肪酸结合蛋白 4 和脂蛋白脂肪酶。进一步的研究表明，核受体共激活因子腺病毒早期区域 1-A 样分化抑制剂 1（EID-1）的表达与 miR-138 呈负相关，当 hAD-MSCs 分化为脂肪细胞时。通过 RNA 干扰敲低 EID-1 抑制 hAD-MSCs 的脂肪细胞分化。此外，荧光素酶报告基因检测表明，miR-138 直接靶向 EID-1 的 3'非翻译区，表明 miR-138 在 hAD-MSCs 脂肪细胞分化中的负作用至少部分是通过抑制 EID-1 介导的。综上所述，本研究表明 miR-138 在成脂分化中起负作用，并揭示了 miRNA 在 hAD-MSCs 向脂肪细胞分化过程中的作用。
