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Cited by 235Extracellular vesicles in diseaseMicroRNA in disease regulationMesenchymal stem cell research

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Altered MicroRNA Expression Profile in Exosomes during Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

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Xu, Ji-Feng, Yang, Guang-hai, Pan, Xiao-Hong, Zhang, Shui-Jun, Zhao, Chen, Qiu, Bin-Song, Gu, Hai-Feng, Hong, Jian-Fei, Cao, Li, Chen, Yu, Xia, Bing, Bi, Qin, Wang, Ya-Ping·2014·PLoS ONE
DOI 10.1371/journal.pone.0114627PMC PMC4263734
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Abstract

The physiological role of microRNAs (miRNAs) in osteoblast differentiation remains elusive. Exosomal miRNAs isolated from human bone marrow-derived mesenchymal stem cells (BMSCs) culture were profiled using miRNA arrays containing probes for 894 human matured miRNAs. Seventy-nine miRNAs (∼8.84%) could be detected in exosomes isolated from BMSC culture supernatants when normalized to endogenous control genes RNU44. Among them, nine exosomal miRNAs were up regulated and 4 miRNAs were under regulated significantly (Relative fold>2, p<0.05) when compared with the values at 0 day with maximum changes at 1 to 7 days. Five miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) were further validated and differentially expressed in the individual exosomal samples from hBMSCs cultured at different time points. Bioinformatic analysis by DIANA-mirPath demonstrated that RNA degradation, mRNA surveillance pathway, Wnt signaling pathway, RNA transport were the most prominent pathways enriched in quantiles with differential exosomal miRNA patterns related to osteogenic differentiation. These data demonstrated exosomal miRNA is a regulator of osteoblast differentiation.

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Figure 1 miRNAs were differentially expressed in exosomes during osteogenic differentiation of human BMSCs. Heatmap representation of the mean fold change in osteogenic differentiation related differential miRNA signature. Two-dimensional grid matrix displaying 5 differential miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) was obtained by the functional heat-map in R. Columns refer to time course comparison: human BMSC culture at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 7 days. Rows stand for the 5 differential miRNAs. Each entry of the grid refers to relative fold (log2) between the expression level of a given miRNA in exosome relative to RNU44 in human BMSCs. The color of each entry is determined by the value of that fold difference, ranging from red (negative values) to yellow (positive values).
Figure 1 miRNAs were differentially expressed in exosomes during osteogenic differentiation of human BMSCs. Heatmap representation of the mean fold change in osteogenic differentiation related differential miRNA signature. Two-dimensional grid matrix displaying 5 differential miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) was obtained by the functional heat-map in R. Columns refer to time course comparison: human BMSC culture at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 7 days. Rows stand for the 5 differential miRNAs. Each entry of the grid refers to relative fold (log2) between the expression level of a given miRNA in exosome relative to RNU44 in human BMSCs. The color of each entry is determined by the value of that fold difference, ranging from red (negative values) to yellow (positive values).CC BY · PubMed Central
Figure 2 Validation of miRNA array expression using independent samples. TaqMan real-time RT-PCR to validate the expression levels of nine up regulated miRNAs, including let-7a, miR-199b, miR-218, miR-148a, miR-135b, miR-203, miR-219, miR-299-5p, and miR-302b (A) and three down regulated miRNAs, including miR-885-5p, miR-181a, and miR-320c (B) from miRNA array were selected for further validation using individual exosomal samples from BMSCs when cultured at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 7 days. Data shown are representative of three independent experiments and are shown as mean ± SEM.
Figure 2 Validation of miRNA array expression using independent samples. TaqMan real-time RT-PCR to validate the expression levels of nine up regulated miRNAs, including let-7a, miR-199b, miR-218, miR-148a, miR-135b, miR-203, miR-219, miR-299-5p, and miR-302b (A) and three down regulated miRNAs, including miR-885-5p, miR-181a, and miR-320c (B) from miRNA array were selected for further validation using individual exosomal samples from BMSCs when cultured at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 7 days. Data shown are representative of three independent experiments and are shown as mean ± SEM.CC BY · PubMed Central
Figure 3 Diagram of RNA degradation. Four differentially expressed miRNAs (including miR-203, miR-299-5p, miR-885-5p, and miR-320c) were selected as examples for examining miRNA-mRNA relationships in RNA degradation.
Figure 3 Diagram of RNA degradation. Four differentially expressed miRNAs (including miR-203, miR-299-5p, miR-885-5p, and miR-320c) were selected as examples for examining miRNA-mRNA relationships in RNA degradation.CC BY · PubMed Central
Figure 4 Diagram of RNA transport. Three under-expressed miRNAs (miR-203, miR-885-5p, and miR-320c) were predicted to participate in RNA transport pathway through regulating their potential gene targets.
Figure 4 Diagram of RNA transport. Three under-expressed miRNAs (miR-203, miR-885-5p, and miR-320c) were predicted to participate in RNA transport pathway through regulating their potential gene targets.CC BY · PubMed Central
Figure 5 Diagram of Wnt signaling pathway. Four differentially expressed miRNAs (including miR-203, miR-299-5p, miR-885-5p, and miR-320c) were predicted to participate in Wnt signaling pathway through regulating their potential gene targets.
Figure 5 Diagram of Wnt signaling pathway. Four differentially expressed miRNAs (including miR-203, miR-299-5p, miR-885-5p, and miR-320c) were predicted to participate in Wnt signaling pathway through regulating their potential gene targets.CC BY · PubMed Central
Figure 6 mRNA transcripts in exosomes during osteogenic differentiation of human BMSCs. Seven mRNAs (RPS2, DGKA, ACIN1, DKK2, Xsox17, DDX6, and Lsm2) were selected for qRT-PCR experiments using BSMC exosomal RNA from twelve independent subjects. In addition, qRT-PCR to detect the expression levels of ADAM17 and NFκB1 in exosomes from the osteogenic differentiated BSMCs. Data shown are representative of three independent experiments and are shown as mean ± SEM.
Figure 6 mRNA transcripts in exosomes during osteogenic differentiation of human BMSCs. Seven mRNAs (RPS2, DGKA, ACIN1, DKK2, Xsox17, DDX6, and Lsm2) were selected for qRT-PCR experiments using BSMC exosomal RNA from twelve independent subjects. In addition, qRT-PCR to detect the expression levels of ADAM17 and NFκB1 in exosomes from the osteogenic differentiated BSMCs. Data shown are representative of three independent experiments and are shown as mean ± SEM.CC BY · PubMed Central
Figure 7 miR-885-5p regulates BMP2-induced osteogenic differentiation. (A). RT-qPCR to detect the expression of Wnt5 mRNA level when miR-885-5p over expression. Data shown are representative of three independent experiments and are shown as mean ± SEM. (B). Western Blot to detect Runx2 protein level in BSMCs were treated with BMP2 for 24 and 48 h after expressing miR-885-5p and miR-Control for 24, 48 h. Data shown are representative of three independent experiments.
Figure 7 miR-885-5p regulates BMP2-induced osteogenic differentiation. (A). RT-qPCR to detect the expression of Wnt5 mRNA level when miR-885-5p over expression. Data shown are representative of three independent experiments and are shown as mean ± SEM. (B). Western Blot to detect Runx2 protein level in BSMCs were treated with BMP2 for 24 and 48 h after expressing miR-885-5p and miR-Control for 24, 48 h. Data shown are representative of three independent experiments.CC BY · PubMed Central

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Authors
Xu, J.-F., Yang, G.-H., Pan, X.-H., Zhang, S.-J., Zhao, C., Qiu, B.-S., Gu, H.-F., Hong, J.-F., Cao, L., Chen, Y., Xia, B., Bi, Q., & Wang, Y.-P.
Affiliations
Zhejiang Provincial People's Hospital (CN)
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-12-11
Volume
9
Issue
12
Pages
e114627
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0114627
PMC
PMC4263734
OpenAlex
W2005323891
Cited by
235
References
60
Citations by year
2026: 4 · 2025: 13 · 2024: 20 · 2023: 15 · 2022: 18 · 2021: 32 · 2020: 26 · 2019: 26 · 2018: 27 · 2017: 28 · 2016: 19 · 2015: 6
FWCI
5.98
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Natural Science Foundation of China (Grant No. 81200113, 81200113)
  • Medical Scientific Research Foundation of Zhejiang Province, China (2013KYB031, Grant No. 2013KYB031)
  • Fundamental Research Funds for the Central Universities (Grant No. 2014FZA7014)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
Keywords
microRNA, exosomes, osteogenic differentiation, bone marrow-derived mesenchymal stem cells, miR-199b, miR-218, miR-148a, miR-135b, miR-221, Wnt signaling, mRNA surveillance, RNA transport, extracellular vesicles
MeSH terms
Adult, Cell Differentiation, Female, Humans, Male, Osteogenesis, RNA, Messenger, Reproducibility of Results, MicroRNAs, Exosomes, Bone Morphogenetic Protein 2, Transcriptome, Mesenchymal Stem Cells

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