Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury
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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ABSTRACT: Mesenchymal stromal cells (MSCs) have been proposed for delivering anticancer agents because of their ability to home tumor microenvironment. We found that MSCs can acquire strong anti-tumor activity after priming with Paclitaxel (PTX) through their capacity to uptake and then release the drug. Because MSCs secrete a high amount of membrane microvesicles (MVs), we here investigated the role of MVs in the releasing mechanism of PTX. The murine SR4987 line was used as MSCs model. The release of PTX from SR4987 in the conditioned medium (CM) was checked by HPLC and the anti-tumor activity of both CM and MVs was tested on the human pancreatic cell line CFPAC-1. MVs were isolated by ultracentrifugation, analysed by transmission (TEM) and scanning electron microscopy (SEM), and the presence of PTX by the Fourier transformed infrared (FTIR) microspectroscopy. SR4987 loaded with PTX (SR4987PTX) secreted a significant amount of PTX and their CM possessed strong anti-proliferative activity on CFPAC-1. At TEM and SEM, SR4987PTX showed an increased number of "vacuole-like" structures and shed a relevant number of MVs, but do not differ from untreated SR4987. However, SR4987PTX-derived-MVs (SR4987PTX-MVs) demonstrated a strong anti proliferative activity on CFPAC-1. FTIR analysis of SR4987PTX-MVs showed the presence of an absorption spectrum in the corresponding regions of PTX marker, absents in MVs from SR4987. Our work is the first demonstration that MSCs are able to package and delivery active drugs through their MVs, suggesting the possibility of using MSCs as a factory to develop drugs with a higher cell-target specificity.Journal of Controlled Release 07/2014; 192. DOI:10.1016/j.jconrel.2014.07.042 · 7.26 Impact Factor
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ABSTRACT: Recent approaches of regenerative medicine can offer a therapeutic option for patients undergoing acute kidney injury. In particular, mesenchymal stem cells were shown to ameliorate renal function and recovery after acute damage. We here evaluated the protective effect and localization of CD133+ renal progenitors from the human inner medulla in a model of glycerol-induced acute tubular damage and we compared the results with those obtained with bone marrow-derived mesenchymal stem cells. We found that CD133+ progenitor cells promoted the recovery of renal function, preventing tubular cell necrosis and stimulating resident cell proliferation and survival, similar to mesenchymal stem cells. In addition, by optical imaging analysis, CD133+ progenitor cells accumulated within the renal tissue, and a reduced entrapment in lung, spleen, and liver was observed. Mesenchymal stem cells were detectable at similar levels in the renal tissue, but a higher signal was present in extrarenal organs. Both cell types produced several cytokines/growth factors, suggesting that a combination of different mediators is involved in their biological action. These results indicate that human CD133+ progenitor cells are renotropic and able to improve renal regeneration in acute kidney injury.05/2014; 2(5). DOI:10.14814/phy2.12009
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ABSTRACT: Diminishing sperm quality during cryopreservation process ends up in a complete or partial loss of sperm's fertilizing potential. Rehabilitation of such affected sperm is crucial to improve their fertilizing potential. A variety of evidence has indicated that secreted microvesicles (MVs) from mesenchymal stem cells (MSCs) are involved in regeneration of injured endogenous cells via shuttling MSC trophic molecules. Sperm obtained from cauda epididymides of adult male Wistar rats were equally assigned to four separate groups. Following suspension in cryoprotectant extender, sperm were untreated or treated with increasing concentrations of MSC-derived MVs (25, 50 and 100μg). After incubation in successive steps, sperm were cryopreserved. The frozen-thawed sperm were assessed for viability, motility and antioxidant capacity parameters. Consequently, expression levels of surface adhesion molecules (CD29, CD44, ICAM-I and VCAM-I) involved in sperm fusogenic and signaling properties, were assessed by flow cytometry. Results showed an enhanced quality parameters and adhesive properties of cryopreserved sperm following treatment with MSC-derived MVs.Reproductive Toxicology 08/2013; 42:78-84. DOI:10.1016/j.reprotox.2013.07.024 · 2.77 Impact Factor