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一个包含miR-26a、糖原合成酶激酶3β（GSK3β）和CCAAT增强子结合蛋白α（C/EBPα）的调控环路调节人脂肪来源间充质干细胞的成骨作用。

A regulatory loop containing miR-26a, GSK3β and C/EBPα regulates the osteogenesis of human adipose-derived mesenchymal stem cells.

作者信息

Wang Zi, Xie Qing, Yu Zhang, Zhou Huifang, Huang Yazhuo, Bi Xiaoping, Wang Yefei, Shi Wodong, Sun Hao, Gu Ping, Fan Xianqun

机构信息

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P.R. China.

出版信息

Sci Rep. 2015 Oct 15;5:15280. doi: 10.1038/srep15280.

DOI:10.1038/srep15280
PMID:26469406
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4606799/
Abstract

Elucidating the molecular mechanisms responsible for osteogenesis of human adipose-derived mesenchymal stem cells (hADSCs) will provide deeper insights into the regulatory mechanisms of this process and help develop more efficient methods for cell-based therapies. In this study, we analysed the role of miR-26a in the regulation of hADSC osteogenesis. The endogenous expression of miR-26a increased during the osteogenic differentiation. The overexpression of miR-26a promoted hADSC osteogenesis, whereas osteogenesis was repressed by miR-26a knockdown. Additionally, miR-26a directly targeted the 3'UTR of the GSK3β, suppressing the expression of GSK3β protein. Similar to the effect of overexpressing miR-26a, the knockdown of GSK3β promoted osteogenic differentiation, whereas GSK3β overexpression inhibited this process, suggesting that GSK3β acted as a negative regulator of hADSC osteogenesis. Furthermore, GSK3β influences Wnt signalling pathway by regulating β-catenin, and subsequently altered the expression of its downstream target C/EBPα. In turn, C/EBPα transcriptionally regulated the expression of miR-26a by physically binding to the CTDSPL promoter region. Taken together, our data identified a novel feedback regulatory circuitry composed of miR-26a, GSK3β and C/EBPα, the function of which might contribute to the regulation of hADSC osteogenesis. Our findings provided new insights into the function of miR-26a and the mechanisms underlying osteogenesis of hADSCs.

摘要

阐明人类脂肪来源间充质干细胞（hADSCs）成骨作用的分子机制，将为这一过程的调控机制提供更深入的见解，并有助于开发更有效的基于细胞的治疗方法。在本研究中，我们分析了miR-26a在hADSCs成骨调控中的作用。miR-26a的内源性表达在成骨分化过程中增加。miR-26a的过表达促进了hADSCs的成骨作用，而miR-26a敲低则抑制了成骨作用。此外，miR-26a直接靶向GSK3β的3'UTR，抑制GSK3β蛋白的表达。与过表达miR-26a的效果相似，敲低GSK3β促进了成骨分化，而GSK3β过表达则抑制了这一过程，表明GSK3β作为hADSCs成骨的负调节因子。此外，GSK3β通过调节β-连环蛋白影响Wnt信号通路，随后改变其下游靶点C/EBPα的表达。反过来，C/EBPα通过与CTDSPL启动子区域物理结合，转录调控miR-26a的表达。综上所述，我们的数据确定了一个由miR-26a、GSK3β和C/EBPα组成的新型反馈调节回路，其功能可能有助于hADSCs成骨的调控。我们的研究结果为miR-26a的功能以及hADSCs成骨的潜在机制提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/ae3fdacf4219/srep15280-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/0452d13e440a/srep15280-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/3927af4828e2/srep15280-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/d273f9975572/srep15280-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/713ce2ba6c6d/srep15280-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/a4e18952b2e2/srep15280-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/19d4c9694b78/srep15280-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/ae3fdacf4219/srep15280-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/0452d13e440a/srep15280-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/3927af4828e2/srep15280-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/d273f9975572/srep15280-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/713ce2ba6c6d/srep15280-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/a4e18952b2e2/srep15280-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/19d4c9694b78/srep15280-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1207/4606799/ae3fdacf4219/srep15280-f7.jpg

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