Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Maria Ines Almeida, Andreia Machado Silva, Daniel Marques Vasconcelos, Catarina Rodrigues Almeida, Hugo Caires, Marta Teixeira Pinto, George Adrian Calin, Susana Gomes Santos and Mário Adolfo Barbosa _

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Abstract

Maria Ines Almeida1,2, Andreia Machado Silva1,2,3, Daniel Marques Vasconcelos1,2,3, Catarina Rodrigues Almeida1,2, Hugo Caires1,2, Marta Teixeira Pinto1,4, George Adrian Calin5, Susana Gomes Santos1,2,3 and Mário Adolfo Barbosa1,2,3

1 Instituto de Investigação e Inovação em Saúde/Institute for Research and Innovation in Health (I3S), University of Porto, Porto, Portugal

2 Instituto de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal

3 Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal

4 Institute of Molecular Pathology and Immunology of University of Porto (Ipatimup), Porto, Portugal

5 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Maria Ines Almeida, email:

Keywords: microRNAs, mesenchymal stromal/stem cells, differentiation, angiogenesis, VEGF, Gerotarget

Received: July 30, 2015 Accepted: November 28, 2015 Published: December 13, 2015

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.


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