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.
Highlights
During bone regeneration, three main phases, inflammation, new bone formation and bone remodeling take place in an orchestrated fashion to repair the injury
With the aim to explore miRNAs involved in the bone regeneration process, we started by performing a miRNA expression profile by microarrays along osteogenic differentiation
New clinical strategies are currently being developed to improve bone regeneration and, among those, modulation of miRNA levels has been investigated [13]. Beyond their role as regulators of the immune response, Mesenchymal Stromal/Stem Cells (MSC) therapeutic effect for bone regeneration is likely related to their capacity to proliferate, undergo osteogenic differentiation and control angiogenesis [22]
Summary
Three main phases, inflammation, new bone formation and bone remodeling take place in an orchestrated fashion to repair the injury. MSC are present in bone marrow and in several connective tissues [1, 2] and can be isolated and expanded in vitro. Modulation of gene expression of MSC at the bone fracture site is emerging as an attractive approach for the improvement of bone fracture healing and for the therapy of bone-related diseases [5, 8]. Such strategy would be important for the elderly population who have an increased risk of bone fractures and have their bone regenerative capacity compromised [9]
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