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      Long non-coding RNA HIF1A-AS2 facilitates adipose-derived stem cells (ASCs) osteogenic differentiation through miR-665/IL6 axis via PI3K/Akt signaling pathway

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          Abstract

          Background

          This study was aimed to investigate the role and specific molecular mechanism of HIF1A-AS2/miR-665/IL6 axis in regulating osteogenic differentiation of adipose-derived stem cells (ASCs) via the PI3K/Akt signaling pathway.

          Methods

          RNAs’ expression profile in normal/osteogenic differentiation-induced ASCs (osteogenic group) was from the Gene Expression Omnibus database. The analysis was carried out using Bioconductor of R. Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes dataset were applied to identify up- and downregulated signaling pathways. Co-expression network of specific lncRNAs and mRNAs was structured by Cytoscape, while binding sites amongst lncRNA, mRNA, and miRNA were predicted by TargetScan and miRanda. ASCs were derived from human adipose tissue and were authenticated by flow cytometry. ASC cell function was surveyed by alizarin red and alkaline phosphatase (ALP) staining. Molecular mechanism of HIF1A-AS2/miR-665/IL6 axis was investigated by RNAi, cell transfection, western blot, and qRT-PCR. RNA target relationships were validated by dual-luciferase assay.

          Results

          HIF1A-AS2 and IL6 were highly expressed while miR-665 was lowly expressed in induced ASCs. HIF1A-AS2 and IL6 improved the expression level of osteoblast markers Runx2, Osterix, and Osteocalcin and also accelerated the formation of calcium nodule and ALP activity, yet miR-665 had opposite effects. HIF1A-AS2 directly targeted miR-665, whereas miR-665 repressed IL6 expression. Moreover, the HIF1A-AS2/miR-665/IL6 regulating axis activated the PI3K/Akt signaling pathway.

          Conclusions

          LncRNA HIF1A-AS2 could sponge miR-665 and hence upregulate IL6, activate the PI3K/Akt signaling pathway, and ultimately promote ASC osteogenic differentiation.

          Electronic supplementary material

          The online version of this article (10.1186/s13287-018-1082-z) contains supplementary material, which is available to authorized users.

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          Most cited references34

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          Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures.

          Claudine Seeliger, K F Karpinski, Helen Vester … (2014)
          Osteoporosis as a systemic skeletal disorder is characterized by increased bone fragility and the risk of fractures. According to the World Health Organization, osteoporosis is one of the 10 most common diseases and affects approximately 75 million people in Europe, the United States, and Japan. In this context, the identification of specific microRNA (miRNA) signatures is an important step for new diagnostic and therapeutic approaches. The focus of interest on miRNAs as biomarkers came with new publications identifying free circulating extracellular miRNAs associated with various types of cancer. This study aimed to identify specific miRNAs in patients with osteoporotic fractures compared with nonosteoporotic fractures. For the array analysis, miRNAs were isolated from the serum of 20 patients with hip fractures, transcribed, and the samples were pooled into 10 osteoporotic and 10 nonosteoporotic specimens. With each pool of samples, human serum and plasma miRNA PCR arrays were performed, which are able to identify 83 different miRNAs. Subsequently, a separate validation analysis of each miRNA found to be regulated in the array followed with miRNA samples isolated from the serum of 30 osteoporotic and 30 nonosteoporotic patients and miRNA samples isolated from the bone tissue of 20 osteoporotic and 20 nonosteoporotic patients. With the validation analysis of the regulated miRNAs, we identified 9 miRNAs, namely miR-21, miR-23a, miR-24, miR-93, miR-100, miR-122a, miR-124a, miR-125b, and miR-148a, that were significantly upregulated in the serum of patients with osteoporosis. In the bone tissue of osteoporotic patients, we identified that miR-21, miR-23a, miR-24, miR-25, miR-100, and miR-125b displayed a significantly higher expression. A total of 5 miRNAs display an upregulation both in serum and bone tissue. This study reveals an important role for several miRNAs in osteoporotic patients and suggested that they may be used as biomarkers for diagnostic purposes and may be a target for treating bone loss and optimizing fracture healing in osteoporotic patients. © 2014 American Society for Bone and Mineral Research.
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            Interleukin-6: from an inflammatory marker to a target for inflammatory diseases.

            Mercedes Rincon (2012)
            The incidence and diversity of chronic inflammatory diseases is increasing worldwide. However, the complexity of clinical symptoms has made it difficult to develop therapies that provide a substantial improvement for extended periods of time in a wide range of patient groups. Thus, there is a need for new therapies that target inflammatory responses without compromising immune defense. Interleukin (IL)-6, one of the first identified cytokines, has recently been recognized as a potential target in inflammatory disease. Here, I discuss how this cytokine has evolved from being a marker of inflammation to a successful target to control inflammation. I will summarize the results from the recent clinical studies using IL-6 receptor blockade, and describe potential mechanisms by which IL-6 can contribute to the progression of inflammatory diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism.

              Rocky S Tuan, David Kuhn, Richard Smith … (2009)
              Adult human mesenchymal stem cells (MSCs) hold promise for an increasing list of therapeutic uses due to their ease of isolation, expansion, and multi-lineage differentiation potential. To maximize the clinical potential of MSCs, the underlying mechanisms by which MSC functionality is controlled must be understood. We have taken a deconstructive approach to understand the individual components in vitro, namely the role of candidate "stemness" genes. Our recent microarray gene expression profiling data suggest that interleukin-6 (IL-6) may contribute to the maintenance of MSCs in their undifferentiated state. In this study, we showed that IL-6 gene expression is significantly higher in undifferentiated MSCs as compared to their chondrogenic, osteogenic, and adipogenic derivatives. Moreover, we found that MSCs secrete copious amounts of IL-6 protein, which decreases dramatically during osteogenic differentiation. We further evaluated the role of IL-6 for maintenance of MSC "stemness," using a series of functional assays. The data showed that IL-6 is both necessary and sufficient for enhanced MSC proliferation, protects MSCs from apoptosis, inhibits adipogenic and chondrogenic differentiation of MSCs, and increases the rate of in vitro wound healing of MSCs. We further identified ERK1/2 activation as the key pathway through which IL-6 regulates both MSC proliferation and inhibition of differentiation. Taken together, these findings show for the first time that IL-6 maintains the proliferative and undifferentiated state of bone marrow-derived MSCs, an important parameter for the optimization of both in vitro and in vivo manipulation of MSCs. (c) 2009 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                Ruoyu Wu: roywxs@163.com
                Jihao Ruan: jihaoruan@sjtu.edu.cn
                Yongjin Sun: 505170879@qq.com
                Mengyu Liu: myl1995lmy@163.com
                Zhuang Sha: shazhuangxzykdx@163.com
                Cunyi Fan:
                ORCID: http://orcid.org/0000-0003-0689-2866
                +86 021-64369181 , cyfan@sjtu.edu.cn
                Qingkai Wu: +86 021-64369181-8315 , wuqingkai@sjtu.edu.cn
                Journal
                Journal ID (nlm-ta): Stem Cell Res Ther
                Journal ID (iso-abbrev): Stem Cell Res Ther
                Title: Stem Cell Research & Therapy
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1757-6512
                Publication date (Electronic): 13 December 2018
                Publication date PMC-release: 13 December 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 348
                Affiliations
                [1 ]ISNI 0000 0004 1798 5117, GRID grid.412528.8, Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, ; Shanghai, 200233 China
                [2 ]ISNI 0000 0004 1798 5117, GRID grid.412528.8, Department of Orthopaedics, , Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, ; No.600 Yishan Road, Xuhui District, Shanghai, 200233 China
                [3 ]ISNI 0000 0004 1798 5117, GRID grid.412528.8, Department of Obstetrics and Gynecology, , Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, ; Shanghai, 200233 China
                [4 ]ISNI 0000 0000 9927 0537, GRID grid.417303.2, Institute of Nervous System Diseases, Xuzhou Medical University, ; Xuzhou, 221004 Jiangsu China
                Author information
                http://orcid.org/0000-0003-0689-2866
                Article
                Publisher ID: 1082
                DOI: 10.1186/s13287-018-1082-z
                PMC ID: 6293597
                PubMed ID: 30545407
                SO-VID: d3415a6a-2045-436e-bf15-273f90acac3a
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 15 August 2018
                Date revision received : 10 October 2018
                Date accepted : 19 November 2018
                Funding
                Funded by: National Natural Science Foundation
                Award ID: 81771523,81472110
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Molecular medicine
                Keywords: hif1a-as2,mir-665,il6,asc,osteogenic differentiation
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: hif1a-as2, mir-665, il6, asc, osteogenic differentiation

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