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Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury

Stefania Bruno^*, Cristina Grange^*, Maria Chiara Deregibus^*, Raffaele A. Calogero, Silvia Saviozzi, Federica Collino^*, Laura Morando^*, Alessandro Busca, Michele Falda, Benedetta Bussolati^*, Ciro Tetta and Giovanni Camussi^*

^* Department of Internal Medicine, Research Center for Experimental Medicine and Center for Molecular Biotechnology, and Department of Clinical and Biological Sciences, University of Torino, Torino, Italy; Bone Marrow Transplant Unit, Haematological Division, San Giovanni Battista Hospital, Torino; Fresenius Medical Care, Bad Homburg, Germany

Correspondence: Dr. G. Camussi, Dipartimento di Medicina Interna, Ospedale Maggiore S. Giovanni Battista, Corso Dogliotti 14, 10126, Torino, Italy. Phone: +39-011-6336708; Fax: +39-011-6631184; E-mail: giovanni.camussi{at}unito.it

Received for publication July 29, 2008. Accepted for publication December 30, 2008.

Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI). The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44- and β1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673