microRNA-320/RUNX2 axis regulates adipocytic differentiation of human mesenchymal (skeletal) stem cells

Hamam, Dana; Ali, Dalia; Vishnubalaji, Radhakrishnan; Hamam, Rimi; Al-Nbaheen, May; Chen, Li; Kassem, Moustapha; Aldahmash, Abdullah; Alajez, Nehad M.

doi:10.1038/cddis.2014.462

Cited by 130 publications

(98 citation statements)

References 54 publications

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“…miR-320a overexpression significantly reduced osteoblastic differentiation, whereas miR-320a inhibition had the opposite effects. It is reported that miR-320 family members are upregulated during adipocyte differentiation of hMSCs, and overexpression of miR-320c promotes adipocytic differentiation of hMSCs [32]. This study together with our findings showing that miR-320a inhibits osteogenesis supports a role for miR-320 in cell lineage determination by promoting the adipogenic and inhibiting the osteogenic phenotype.…”

Section: Discussionsupporting

confidence: 71%

MicroRNA-320a Regulates the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Targeting HOXA10

Huang¹,

Meng

Liu

et al. 2016

Cell Physiol Biochem

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Background/Aims: Human bone marrow-derived mesenchymal stem cells (hMSCs) are a promising cell source for bone engineering owing to their high potential to differentiate into osteoblasts. The bone morphogenetic protein-inducible gene homeobox a10 (HOXA10) is a critical regulator of osteogenesis. The objective of the present study was to identify microR-NAs (miRNAs) targeting HOXA10 and examine the effects on the osteogenic differentiation of hMSCs. Methods: Based on in silico analysis, HOXA10-targeting miRNAs were selected and their regulatory roles in osteoblast differentiation were investigated. Results: Six HOXA10-targeting miRNAs were identifIed by computational analysis, of which miR-320a was selected for further analysis because it was downregulated during osteogenic induction. Overexpression of miR-320a downregulated HOXA10 and significantly inhibited osteogenesis in hMSCs, as determined by the downregulation of the osteogenic markers Runx2, ALP, and OC and the inhibition of ALP activity and matrix mineralization, whereas miR-320a inhibition had the opposite effects. Furthermore, ectopic expression of HOXA10 (not including 3′-UTR) rescued the effects of miR-320a on osteogenic differentiation. Conclusion: These results suggest that miR-320a acts as a critical regulator of osteogenic differentiation of hMSCs by repressing its target HOXA10.

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Section: Discussionsupporting

confidence: 71%

MicroRNA-320a Regulates the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Targeting HOXA10

Huang¹,

Meng

Liu

et al. 2016

Cell Physiol Biochem

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“…miR-125b-5p, miR-30e-3p and miR-204-5p), whereas several of them (e.g. miR-93-5p and miR-203-3p) had been reported to negatively regulate osteogenesis (Table S3) (Kennell et al, 2008;Hamam et al, 2014;Yang et al, 2012;. Eguchi et al also analyzed the miRNAs in adipocytes derived from EVs and detected several adipogenic miRNAs (including miR-148a-3p, miR-181a-5p, miR30a-5p, miR-125b-5p) (Eguchi et al, 2016), which is consistent with our results (Table S3).…”

Section: Discussionmentioning

confidence: 99%

“…For example, miR-30a is a positive regulator of adipocyte lineage commitment that acts through modulation of Runx2 while miR-143 is required for terminal differentiation by modulating MAP2K5-ERK5 (ERK5 is also known as MAPK7) signaling Chen et al, 2014;Hamam et al, 2014). In addition, exosomal miRNAs also contribute to the process of cell differentiation (Forterre et al, 2014;Xu et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

miR-450a-5p within rat adipose tissue exosome-like vesicles promotes adipogenic differentiation by targeting WISP2

Zhang

Dai

et al. 2017

Journal of Cell Science

100

103

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Adipose tissue is an active endocrine organ that can secrete a wide number of factors to regulate adipogenesis via paracrine signals. In addition to soluble proteins in adipose tissue, microRNAs (miRNAs) enriched in extracellular vesicles (EVs), such as exosomes or microvesicles, could modulate intercellular communications. In this study, we demonstrated that exosome-like vesicles derived from adipose tissue (Exo-AT) were internalized by adipose tissue-derived stem cells (ADSCs), and that these, in turn, induced adipogenesis. High-throughput sequencing showed that 45 miRNAs were enriched in Exo-AT, and 31.11% of them were associated with adipogenesis, compared with ADSC-derived exosome-like vesicles (Exo-ADSC). miR-450a-5p, one of the most abundant miRNAs in Exo-AT, was a proadipogenic miRNA. Further study demonstrated that miR-450a-5p promoted adipogenesis through repressing expression of WISP2 by targeting its 3′ untranslated region. Additionally, Exo-AT could also downregulate the expression of WISP2, while miR-450a-5p inhibitor reversed this effect. Moreover, inhibition of miR-450a-5p impaired adipogenesis mediated by exosome-like vesicles. In conclusion, Exo-AT mediates adipogenic differentiation through a mechanism involving transfer of miR-450a-5p.

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“…For example, miR-196a, miR-335-5p, miR-322, miR-26a, miR-26b, miR-29b, miR-1192, miR-218, miR-378, miR-548d-5p and miR-302a accelerate osteogenic differentiation [14][15][16][17][18][19][20][21][22], while miR-26a, miR-133, miR-135b, miR-138, the miR-30 family, miR-155, miR-100, miR-433, miR-145, miR-143, miR-542-3p, miR-338-3p, miR-140-5p and miR-146a impair osteoblast differentiation [23][24][25][26][27][28][29][30][31][32][33][34][35]. Many miRNAs have been reported to be involved in the regulation of adipogenic differentiation, such as miR-143, miR-17-92, miR-130, miR-138, miR-17-5p, miR-106a, miR-210, miR-709, miR-137, and miR-302 [36][37][38][39][40][41][42][43][44]. However, few miRNAs have been reported in association with obesity and the positive regulation of adipogenesis [45].…”

Section: Introductionmentioning

confidence: 99%

Obesity-Associated MiR-342-3p Promotes Adipogenesis of Mesenchymal Stem Cells by Suppressing CtBP2 and Releasing C/EBPα from CtBP2 Binding

Wang

et al. 2015

Cell Physiol Biochem

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Background/Aims: The elucidation of the molecular mechanism of adipocyte differentiation in mesenchymal stem cells is of essential importance for the development of treatments for metabolic diseases, such as obesity and diabetes. Methods: The expression levels of miR-342-3p and carboxy-terminal binding protein 2 (CtBP2) were regulated by oligonucleotide transfection. Adipogenic differentiation was induced by adipogenic medium containing indomethacin, dexamethasone and 3-isobutyl-1-methylxanthine on day 12, as determined by Oil Red O staining and triglyceride concentration assay to assess intracellular lipid accumulation. The induction of adipocyte-specific transcription factors and markers was detected by qRT-PCR and western blot. The regulation of CtBP2 expression by miR-342-3p was determined by western blot, qRT-PCR, luciferase reporter assay, ChIP assay and functional experiments. Results: We revealed that miR-342-3p was enriched in the adipose tissue of obese mice, and its expression was significantly elevated during adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3L1 cells. Using gain- and loss-of-function assays, we demonstrated that the overexpression of miR-342-3p markedly promoted the differentiation of hMSCs into an adipogenic lineage. Adipogenesis was significantly blocked by miR-342-3p downregulation. We identified and validated that CtBP2 was a direct target of miR-342-3p in this process. The effects of the inhibition of CtBP2 were similar to those of miR-342-5p overexpression on adipogenic differentiation, promoting the release of C/EBPα from CtBP2 binding. Conclusion: miR-342-3p is a powerful enhancer of the adipogenesis of human adipose-derived MSCs that acts by inhibiting CtBP2 and releasing the key adipogenic regulator C/EBPα from CtBP2 binding, subsequently activating the expression of adipogenic transcription factors and markers.

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microRNA-320/RUNX2 axis regulates adipocytic differentiation of human mesenchymal (skeletal) stem cells

Cited by 130 publications

References 54 publications

MicroRNA-320a Regulates the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Targeting HOXA10

MicroRNA-320a Regulates the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Targeting HOXA10

miR-450a-5p within rat adipose tissue exosome-like vesicles promotes adipogenic differentiation by targeting WISP2

Obesity-Associated MiR-342-3p Promotes Adipogenesis of Mesenchymal Stem Cells by Suppressing CtBP2 and Releasing C/EBPα from CtBP2 Binding

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