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: 9.34). 05/2009; 20(5):1053-67. DOI: 10.1681/ASN.2008070798
Source: PubMed


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 MVs were also analyzed by flow cytometry using an Attune Acoustic Focusing Cytometer (Applied Biosystems). Attune Performance Tracking Beads (2.4 and 3.2 mm, Applied Biosystems) and NAD cells were used as size markers, and the analysis was performed using a log scale for forward scatter and side scatter parameters as described previously (Bruno et al., 2009 "
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    ABSTRACT: The ability of bone marrow-derived mononuclear cells (BMMCs) to differentiate into hepatocyte-like cells under different conditions has been demonstrated previously. In the present study, we investigated the effect of CCl4-injured hepatocytes on the differentiation of the non-adherent (NAD) fraction of BMMCs. Differentiation (cell fate) was analyzed after 2, 6 and 24h of co-culture by gene and protein expression and by urea production. We also evaluated the presence of microvesicles (MVs) in the supernatant of differentiated cells, their content and the ability of these cells to absorb them. Hepatocyte-like characteristics were observed in the NAD cells after 24h of co-culture with injured hepatocytes. Cells that were co-cultured with healthy hepatocytes did not present signs of differentiation at any analyzed time point. Analysis of the supernatant from differentiated cells revealed the presence of MVs carrying hepatocyte-specific mRNAs, including Albumin, Coagulation factor V, Alpha-fetoprotein, and Cytokeratin 18. The incorporation of injured hepatocyte-derived MVs by NAD cells was shown at 24h, suggesting a possible role for MVs in the induction of cell plasticity.
    Differentiation 09/2015; DOI:10.1016/j.diff.2015.09.001 · 3.44 Impact Factor
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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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    ABSTRACT: Cancer treatment plans mainly include chemotherapy, radiotherapy and surgery, which exert serious adverse reactions immediately or during the long term after cancer therapy in many patients. In several cases, treatment-related adverse effects outweigh treatment benefits and worsen the patient's condition. This problem is not avoidable with current cancer therapy procedures; therefore, improved understanding and earlier prevention and reversion of treatment-related complications are particularly important before the lesions become progressive and irreversible. Mesenchymal stromal cell therapy is very promising in recent clinical research and investigations. Their potential properties such as regenerative and reparative functions and anti-inflammatory activity make them proper candidates for cell therapy to recover cancer patients from treatment-related adverse effects or may even prevent them. This article discuss benefits of applying human mesenchymal stromal cell therapy after current cancer treatment plans, with the purpose of prevention and healing of adverse reactions, faster patient recovery after radio/chemotherapy, reducing rates of treatment failure and cancer recurrence and increasing patient quality of life after treatment cessation.
    Cytotherapy 01/2015; 17(5). DOI:10.1016/j.jcyt.2014.10.015 · 3.29 Impact Factor
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    • "Mesenchymal stromal cell-EVs also contain nucleic acids (mRNA and non-coding RNA). The mRNAs present in EVs are representative of the multiple differentiation and functional properties of MSCs, including transcripts related to several different cell functions (e.g., the control of transcription, cell proliferation, and immune regulation) (33). EVs from MSCs also contain mRNA for receptors of specific growth factors, such as mRNA for the insulin growth factor 1 (IGF-1) receptor (34). "
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    ABSTRACT: Extracellular vesicles (EVs) are membrane vesicles, which are secreted by a variety of cells that have a relevant role in intercellular communication. EVs derived from various cell types exert different effects on target cells. Mesenchymal stromal cells (MSCs) are stem cells that are ubiquitously present in different tissues of the human body, and MSC-derived EVs take part in a wide range of biological processes. Of particular relevance is the effect of MSCs on tumor growth and progression. MSCs have opposing effects on tumor growth, being able either to favor angiogenesis and tumor initiation, or to inhibit progression of established tumors, according to the conditions. Different studies have reported that EVs from MSCs may exert either an anti- or a pro-tumor growth effect depending on tumor type and stage of development. In this review, we will discuss the data presented in the literature on EV-mediated interactions between MSCs and tumors.
    Frontiers in Immunology 08/2014; 5:382. DOI:10.3389/fimmu.2014.00382
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