title: AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs.
abstract: Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cell-promoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI.
authors.affiliation: Department of Medical Sciences, Translational Center of Regenerative Medicine, Fresenius Medical Care S.p.A..
authors.forename: Federica
authors.initials: F
authors.lastname: Collino
authors.affiliation: Department of Molecular Biotechnology and Healthy Sciences, and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bruno
authors.affiliation: Department of Life Sciences and System Biology and Human Genetics Foundation, University of Torino, Torino, Italy;
authors.forename: Danny
authors.initials: D
authors.lastname: Incarnato
authors.affiliation: Department of Molecular Biotechnology and Healthy Sciences, and Department of Life Sciences and System Biology and Human Genetics Foundation, University of Torino, Torino, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Dettori
authors.affiliation: Department of Life Sciences and System Biology and Human Genetics Foundation, University of Torino, Torino, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Neri
authors.affiliation: Department of Molecular Biotechnology and Healthy Sciences, and Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy; and.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Department of Medical Sciences.
authors.forename: Margherita
authors.initials: M
authors.lastname: Pomatto
authors.affiliation: Department of Life Sciences and System Biology and Human Genetics Foundation, University of Torino, Torino, Italy;
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
authors.affiliation: Translational Center of Regenerative Medicine, Fresenius Medical Care S.p.A., EMEA Fresenius Medical Care, Bad Homburg, Germany;
authors.forename: Ciro
authors.initials: C
authors.lastname: Tetta
authors.affiliation: Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Quesenberry
authors.affiliation: Department of Medical Sciences, giovanni.camussi@unito.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
mesh_terms: D058186:Acute Kidney Injury / Q000628:therapy*; D000818:Animals; D000067128:Extracellular Vesicles; D005260:Female; D059630:Mesenchymal Stem Cells / Q000648:ultrastructure*; D051379:Mice; D035683:MicroRNAs
chemical_list: D035683:MicroRNAs
keywords: acute renal failure; gene expression; stem cell