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.
- SourceAvailable from: Fatemeh Hendijani
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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 . 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 . Immediate injection of MVs obtained from adult MSC after ischemia and reperfusion injury could prevent both acute and chronic kidney disease . "
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; 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 . The paracrine capacity of MSCs appears to be an important mechanism in determining their efficacy when used for regenerative therapies . This has increased the interest in MVs and exosome biology and functions, particularly in exploring the kind of cargo that MVs or exosomes transport. "
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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- "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. "
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