miR-31-5p Is a LIPUS-Mechanosensitive MicroRNA that Targets HIF-1α Signaling and Cytoskeletal Proteins

Abstract

The roles of low-intensity pulsed ultrasound (LIPUS) and microRNAs (miRNAs) on hMSCs commitments have already been investigated; however, the effects of the application of their co-treatments in an in vitro cell model are still unknown. Our previous studies demonstrated that (i) LIPUS modulated hMSCs cytoskeletal organization and (ii) miRNA-675-5p have a role in HIF-1α signaling modulation during hMSCs osteoblast commitment. We investigated for the first time the role of LIPUS as promoter tool for miRNA expression. Thanks to bioinformatic analysis, we identified miR-31-5p as a LIPUS-induced miRNA and investigated its role through in vitro studies of gain and loss of function. Results highlighted that LIPUS stimulation induced a hypoxia adaptive cell response, which determines a reorganization of cell membrane and cytoskeleton proteins. MiR-31-5p gain and loss of function studies, demonstrated as miR-31-5p overexpression, were able to induce hypoxic and cytoskeletal responses. Moreover, the co-treatments LIPUS and miR-31-5p inhibitor abolished the hypoxic responses including angiogenesis and the expression of Rho family proteins. MiR-31-5p was identified as a LIPUS-mechanosensitive miRNAs and may be considered a new therapeutic option to promote or abolish hypoxic response and cytoskeletal organization on hMSCs during the bone regeneration process.

Low-Intensity Pulsed Ultrasound Alleviates Hypoxia-Induced Chondrocyte Damage in Temporomandibular Disorders by Modulating the Hypoxia-Inducible Factor Pathway

“…It has been reported that LIPUS targets miR-31-5p to regulate HIF-1a. However, the mechanism underlying LIPUS regulation of HIF-2a has rarely been reported (Costa et al, 2019). Thus, the mechanism by which LIPUS influences HIF pathways is still unclear and requires further study.…”

MiR-33a Controls hMSCS Osteoblast Commitment Modulating the Yap/Taz Expression Through EGFR Signaling Regulation

“…MicroRNAs (miRNAs) are attractive candidates as multifunctional regulators of bone signaling [6] and have been investigated as new biomarkers of bone disease or regeneration in the last years. In our previous studies, we identified two miRNAs involved in bone regeneration: (i) miRNA-675-5p as a modulator of HIF-1α and Wnt/β-catenin signalings in human mesenchymal stromal cells (hMSCs) [6]; and (ii) miRNA-31-5p, a mechanosensitive miRNA involved in hMSCs hypoxia response [7]. Microarray analysis revealed that hMSCs and osteoblast cells showed strong differences in terms of miRNAs expression and relative signaling activation [8,9], such as epithelial-to-mesenchymal transition (EMT) pathway [9] and the epidermal growth factor (EGF) signaling [10], which are strongly correlated to hypoxia cell response during osteoblast differentiation [6].…”

“…In this study, we wanted to understand the role of the miR-33a family during hMSCs osteoblast commitment and their relative targets using hMSCs as a model of stromal cells, hMSCs maintained in osteogenic medium as a model of pre-osteoblast cells, and Nh-Ost as a model of osteoblast cells [8,9]. Starting from the recent evidence that displayed a different miRNAs expression profiling between hMSCs and Nh-Ost as well as from our previous studies in which we demonstrated the roles of miR-675-5p and miR-31-5p in hypoxia and cytoskeletal modulation during hMSCs osteoblast differentiation [6,7], we decided to investigate another important signaling involved in hMSCs osteoblast commitment, such as EMT, for which it has been demonstrated that miR-33a shows a different mRNAs interaction.…”

The Urinary Exosomal miRNA Expression Profile is Predictive of Clinical Response in Lupus Nephritis

“…The fact that the three identified miRNAs were increased simultaneously in LN responder group suggested that they may share common targets. Hypoxia-inducible factor-1 alpha (HIF-1α) has been reported as common target of them [21][22][23]. HIF-1α is an important player for the development of renal diseases but its role is controversial; whereas it has a protective role promoting cellular adaptation to hypoxia or angiogenesis, it can exacerbate fibrosis in tubular epithelial cells, promote in vivo glomerulosclerosis and mesangial renal proliferation, and contribute to glomerular injury [22][23][24].…”