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MiR-195 in human primary mesenchymal stromal/stem cells regulates proliferation, osteogenesis and paracrine effect on angiogenesis.

ABSTRACT: Mesenchymal Stromal/Stem Cells (MSC) are currently being explored in diverse clinical applications, including regenerative therapies. Their contribution to regeneration of bone fractures is dependent on their capacity to proliferate, undergo osteogenesis and induce angiogenesis. This study aimed to uncover microRNAs capable of concomitantly regulate these mechanisms. Following microRNA array results, we identified miR-195 and miR-497 as downregulated in human primary MSC under osteogenic differentiation. Overexpression of miR-195 or miR-497 in human primary MSC leads to a decrease in osteogenic differentiation and proliferation rate. Conversely, inhibition of miR-195 increased alkaline phosphatase expression and activity and cells proliferation. Then, miR-195 was used to study MSC capacity to recruit blood vessels in vivo. We provide evidence that the paracrine effect of MSC on angiogenesis is diminishedwhen cells over-express miR-195. VEGF may partially mediate this effect, as its expression and secreted protein levels are reduced by miR-195, while increased by anti-miR-195, in human MSC. Luciferase reporter assays revealed a direct interaction between miR-195 and VEGF 3´-UTR in bone cancer cells. In conclusion, our results suggest that miR-195 regulates important mechanisms for bone regeneration, specifically MSC osteogenic differentiation, proliferation and control of angiogenesis; therefore, it is a potential target for clinical bone regenerative therapies.

SUBMITTER: Almeida MI

PROVIDER: S-EPMC4807979 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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miR-195 in human primary mesenchymal stromal/stem cells regulates proliferation, osteogenesis and paracrine effect on angiogenesis.

Almeida Maria Ines MI Silva Andreia Machado AM Vasconcelos Daniel Marques DM Almeida Catarina Rodrigues CR Caires Hugo H Pinto Marta Teixeira MT Calin George Adrian GA Calin George Adrian GA Santos Susana Gomes SG Barbosa Mário Adolfo MA

Oncotarget 20160101 1

Mesenchymal Stromal/Stem Cells (MSC) are currently being explored in diverse clinical applications, including regenerative therapies. Their contribution to regeneration of bone fractures is dependent on their capacity to proliferate, undergo osteogenesis and induce angiogenesis. This study aimed to uncover microRNAs capable of concomitantly regulate these mechanisms. Following microRNA array results, we identified miR-195 and miR-497 as downregulated in human primary MSC under osteogenic differe ...[more]

PMID: 26683705

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Project description:hsa-miR-195-5p (miR-195) has been proven to be a critical regulator in the progression of prostate cancer (PCa). To identify additional targets and molecular functions of miR-195, we overexpressed miR-195 by transient oligonucleotide transfection in DU145 and LNCaP cells and examined the effects. RNA-based microarray and dual-luciferase assays were carried out to identify novel targets of miR-195, while in vitro functional assays, a subcutaneous xenograft model, tissue microarray (TMA) analysis and a cohort of publicly available data (Taylor cohort) were used to investigate the biological function and clinical value of miR-195 targeting. The results shown that miR-195 overexpression could markedly suppress cellular proliferation and tube formation compared with miR-negative control. The RNA-based microarray identified a total of 153 differentially regulated genes with fold changes of ≤|1.5|, including 138 (90.2%) downregulated and 15 (9.8%) upregulated genes. Among the downregulated genes, we found that proline-rich protein 11 (PRR11) combined with miR-195 expression (miR-195/PRR11) could be used as an independent predictor of the risk of biochemical recurrence in the Taylor cohort. Additionally, the dual-luciferase assay identified PRR11 as a novel target of miR-195, and the in vitro assays indicated that PRR11 abrogated the suppressive effects of miR-195 on cell proliferation, tube formation and cell cycling. Furthermore, the subcutaneous tumor xenograft model indicated that knockdown of PRR11 inhibited xenograft growth and angiogenesis, while the results of the TMA and Taylor cohort analyses collectively demonstrated that PRR11 expression was upregulated in aggressive tumors and is associated with poor clinical outcome. Taken together, these findings further illustrate the suppressive role of miR-195 in PCa, and indicate a novel role of PRR11 in PCa. Importantly, the newly identified miR-195/PRR11 axis may aid with identifying potential therapeutic targets in PCa.

Dataset Information

MiR-195 in human primary mesenchymal stromal/stem cells regulates proliferation, osteogenesis and paracrine effect on angiogenesis.

Publications

miR-195 in human primary mesenchymal stromal/stem cells regulates proliferation, osteogenesis and paracrine effect on angiogenesis.

Similar Datasets

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