Pulsed Electromagnetic Fields Modulate miRNAs During Osteogenic Differentiation of Bone Mesenchymal Stem Cells: a Possible Role in the Osteogenic-angiogenic Coupling Monica De Mattei 1 & Silvia Grassilli 2,3 & Agnese Pellati 2 & Federica Brugnoli 2 & Elena De Marchi 1 & Deyanira Contartese 1,4 & Valeria Bertagnolo 2 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Despite the high intrinsic ability of bone tissue to regenerate, bone healing fails in some pathological conditions and especially in the presence of large defects. Due to the strong relationship between bone development and vascularization during in vivo bone formation and repair, strategies promoting the osteogenic-angiogenic coupling are crucial for regenerative medicine. Increasing evidence shows that miRNAs play important roles in controlling osteogenesis and bone vascularization and are important tool in medical research although their clinical use still needs to optimize miRNA stability and delivery. Pulsed electromagnetic fields (PEMFs) have been successfully used to enhance bone repair and their clinical activity has been associated to their ability to promote the osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this study we investigated the potential ability of PEMF exposure to modulate selected miRNAs involved in the osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs). We show that, during in vitro hBMSC differentiation, PEMFs up-modulate the expression of miR-26a and miR-29b, which favor osteogenic differentiation, and decrease miR-125b which acts as an inhibitor miRNA. As PEMFs promote the expression and release of miRNAs also involved in angiogenesis, we conclude that PEMFs may represent a noninvasive and safe strategy to modulate miRNAs with relevant roles in bone repair and with the potential to regulate the osteogenic-angiogenic coupling. Keywords Bone repair . Osteogenic differentiation . Human bone mesenchymal stem cells (hBMSCs) . Pulsed electromagnetic field (PEMF) . miRNAs . Osteogenic-angiogenic coupling Introduction Bone repair is a complex multistep process which involves differentiation of mesenchymal stem cells (MSCs) into osteo- blasts and requires coordinated coupling between osteogene- sis and angiogenesis [1, 2]. Increasing body of evidence supports the crucial role of microRNAs (miRNAs) in bone development and homeostasis [3, 4] and in promoting MSC osteogenic differentiation [5, 6]. Complex interactions among miRNAs coordinate osteogenesis and angiogenesis during de- velopment, remodeling and regeneration of the skeletal sys- tem [7]. The strategies improving bone regeneration include electro- magnetic field (EMF) exposure that, in the last decades, has been applied with beneficial effects in skeletal diseases and ununited fractures [8, 9]. It is widely accepted that EMFs reg- ulate all cells involved in the bone repair processes, including MSCs and osteoblasts [10–13] and animal studies suggest that EMFs promotes the osteogenesis-angiogenesis coupling [8]. EMFs were reported to modulate different phases of oste- ogenic differentiation involving a number of intracellular sig- naling pathways [8]. We previously demonstrated that a pulsed electromagnetic field (PEMF) with specific physical parameters stimulates the osteoblast differentiation of human bone mesenchymal stem cells (hBMSCs) also by increasing * Monica De Mattei monica.demattei@unife.it * Valeria Bertagnolo bgv@unife.it 1 Department of Medical Sciences, University of Ferrara, Ferrara, Italy 2 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy 3 LTTA Centre, University of Ferrara, Ferrara, Italy 4 Laboratory Preclinical and Surgical Studies, IRCCS-Istituto Ortopedico Rizzoli, Bologna, Italy Stem Cell Reviews and Reports https://doi.org/10.1007/s12015-020-10009-6