title: Extracellular vesicles released from mesenchymal stromal cells modulate miRNA in renal tubular cells and inhibit ATP depletion injury.
abstract: The mechanisms involved in renal repair by mesenchymal stromal cells (MSCs) are not entirely elucidated. The paracrine secretion of bioactive molecules has been implicated in the protective effects. Besides soluble mediators, MSCs have been shown to release extracellular vesicles (EVs), involved in renal repair process for different injury models. EVs have been shown to mediate communication between cells through the transference of several molecules, like protein, bioactive lipids, mRNA, and microRNAs (miRNAs). The miRNAs are noncoding RNAs that posttranscriptionally modulate gene expression and are involved in the regulation of several cellular processes, including those related to repair. The aim of the present study was to investigate the role of MSC-EVs in the modulation of miRNAs inside renal proximal tubular epithelial cells (PTECs) in an in vitro model of ischemia-reperfusion injury induced by ATP depletion. In this model we evaluated whether changes in miRNA expression were dependent on direct miRNA transfer or on transcription induction by MSC-EVs. The obtained results showed an enhanced incorporation of MSC-EVs in injured PTECs with protection from cell death. This biological effect was associated with EV-mediated miRNA transfer and with transcriptional modulation of miRNAs expressed by injured PTECs. Prediction of miRNA targets showed that miRNAs modulated in PTECs are involved in process of renal recovery with downregulation of coding-mRNAs associated with apoptosis, cytoskeleton reorganization, and hypoxia, such as CASP3 and 7, SHC1 and SMAD4. In conclusion, these results indicate that MSC-EVs may transfer and modulate the expression of several miRNAs involved in the repair and recovery process in PTECs.
authors.affiliation: 1 Department of Medical Sciences, Molecular Biotechnology Center, University of Torino , Turin, Italy .
authors.forename: Rafael S
authors.initials: RS
authors.lastname: Lindoso
authors.forename: Federica
authors.initials: F
authors.lastname: Collino
authors.forename: Stefania
authors.initials: S
authors.lastname: Bruno
authors.forename: Dayana S
authors.initials: DS
authors.lastname: Araujo
authors.forename: Julliana F
authors.initials: JF
authors.lastname: Sant'Anna
authors.forename: Ciro
authors.initials: C
authors.lastname: Tetta
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Quesenberry
authors.forename: Adalberto
authors.initials: A
authors.lastname: Vieyra
authors.forename: Marcelo
authors.initials: M
authors.lastname: Einicker-Lamas
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency*; D002460:Cell Line; D049109:Cell Proliferation; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D019610:Cytoprotection; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D063990:Gene Ontology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018960:Hyaluronan Receptors; D019012:Integrin beta1; D035683:MicroRNAs; D000255:Adenosine Triphosphate