Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury

Department of Internal Medicine, Research Center for Experimental Medicine, University of Torino, Torino, Italy.
Journal of the American Society of Nephrology (Impact Factor: 9.47). 05/2009; 20(5):1053-67. DOI: 10.1681/ASN.2008070798
Source: PubMed

ABSTRACT 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 beta1-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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    • "The therapeutic role of the MSC secretome has also been reported in a preclinical model of acute renal failure through downregulation of pro-inflammatory molecules such as IL-1b, TNF-a, interferon-g and inducible nitric oxide synthase in treated kidneys and concurrent induction of the anti-inflammatory cytokines IL-10, basic fibroblast growth factor, and TGF-a [180]. Additionally, therapeutic effects of adult MSC-derived microvesicles (MVs) was confirmed in a rat model of acute kidney injury through mRNA transfer, leading to induction of epigenetic changes in the resident host cells, cell cycle restoration and activation of tissue-regenerative programs [181]. Immediate injection of MVs obtained from adult MSC after ischemia and reperfusion injury could prevent both acute and chronic kidney disease [182]. "
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    Cytotherapy 01/2015; DOI:10.1016/j.jcyt.2014.10.015 · 3.10 Impact Factor
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    • "It has been shown that MSCs have a potent paracrine activity and secrete significant quantities of MVs [12]. The paracrine capacity of MSCs appears to be an important mechanism in determining their efficacy when used for regenerative therapies [14]. This has increased the interest in MVs and exosome biology and functions, particularly in exploring the kind of cargo that MVs or exosomes transport. "
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    Journal of Controlled Release 07/2014; 192. DOI:10.1016/j.jconrel.2014.07.042 · 7.26 Impact Factor
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    • "We here found that CD133 + cells, observed at an early time (48 h after their injection), were mainly localized in the interstitium and few cells were also detectable within renal tubular or glomerular structures . However, we only found a limited proliferation of CD133 + cells from the inner medulla, possibly indicating the involvement of paracrine mechanisms, as already described for MSCs (Imberti et al. 2007; Bruno et al. 2009; Gatti et al. 2011). This is also suggested by the lack of acquirement of epithelial or endothelial markers. "
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