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      Bone marrow mesenchymal stem cell-derived exosomes attenuate D-GaIN/LPS-induced hepatocyte apoptosis by activating autophagy in vitro


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          Acute liver failure is an inflammation-mediated hepatocyte injury. Mesenchymal stem cell (MSC) transplantation is currently considered to be an effective treatment strategy for acute liver failure. Exosomes are an important paracrine factor that can be used as a direct therapeutic agent. However, the use of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in the treatment of acute liver failure has not been reported.


          Here, we established a model of hepatocyte injury and apoptosis induced by D-galactosamine and lipopolysaccharide (D-GalN/LPS) to study the protective effect of BMSC-Exos on hepatocyte apoptosis, and further explored its protective mechanism.


          BMSC-Exos was identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. Laser confocal microscopy was used to observe the uptake of Dil-Exos by hepatocytes. D-GalN/LPS-induced primary hepatocytes were pretreated with BMSC-Exos in vitro, and then the cells were harvested. The apoptosis of hepatocytes was observed by TUNEL staining, flow cytometry and Western blot. Electron microscopy and mRFP-GFP-LC3 and Western blot was used to observe autophagy.


          BMSC-Exos increased the expression of autophagy marker proteins LC3 and Beclin-1 and promoted the formation of autophagosomes. After BMSC-Exos treatment, the expression levels of the proapoptotic proteins Bax and cleaved caspase-3 were significantly decreased, while the expression level of the anti-apoptotic protein Bcl-2 was upregulated. However, when the autophagy inhibitor 3MA was present, the effect of BMSC-Exos on inhibiting apoptosis was significantly reversed.


          Our results showed for the first time that BMSC-Exos had the potential to reduce hepatocyte apoptosis after acute liver failure. In particular, we found that BMSC-Exos attenuated hepatocyte apoptosis by promoting autophagy. 

          Most cited references28

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          Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes

          Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ) in the brain because of an imbalance between Aβ production and clearance. Neprilysin (NEP) is the most important Aβ-degrading enzyme in the brain. Thus, researchers have explored virus-mediated NEP gene delivery. However, such strategies may entail unexpected risks, and thus exploration of a new possibility for NEP delivery is also required. Here, we show that human adipose tissue-derived mesenchymal stem cells (ADSCs) secrete exosomes carrying enzymatically active NEP. The NEP-specific activity level of 1 μg protein from ADSC-derived exosomes was equivalent to that of ~ 0.3 ng of recombinant human NEP. Of note, ADSC-derived exosomes were transferred into N2a cells, and were suggested to decrease both secreted and intracellular Aβ levels in the N2a cells. Importantly, these characteristics were more pronounced in ADSCs than bone marrow-derived mesenchymal stem cells, suggesting the therapeutic relevance of ADSC-derived exosomes for AD.
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            Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.

            Under conditions of tissue injury, myocardial replication and regeneration have been reported. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting that marrow serves as a reservoir for cardiac precursor cells. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+-GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates.
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              The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles.

              Extracellular vesicles (EVs), membrane vesicles that are secreted by a variety of mammalian cell types, have been shown to play an important role in intercellular communication. The contents of EVs, including proteins, microRNAs, and mRNAs, vary according to the cell type that secreted them. Accordingly, researchers have demonstrated that EVs derived from various cell types play different roles in biological phenomena. Considering the ubiquitous presence of mesenchymal stem cells (MSCs) in the body, MSC-derived EVs may take part in a wide range of events. In particular, MSCs have recently attracted much attention due to the therapeutic effects of their secretory factors. MSC-derived EVs may therefore provide novel therapeutic approaches. In this review, we first summarize the wide range of functions of EVs released from different cell types, emphasizing that EVs echo the phenotype of their parent cell. Then, we describe the various therapeutic effects of MSCs and pay particular attention to the significance of their paracrine effect. We then survey recent reports on MSC-derived EVs and consider the therapeutic potential of MSC-derived EVs. Finally, we discuss remaining issues that must be addressed before realizing the practical application of MSC-derived EVs, and we provide some suggestions for enhancing their therapeutic efficiency. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                19 August 2019
                : 13
                : 2887-2897
                [1 ]Medical College of Qingdao University , Qingdao 266071, Shandong, People’s Republic of China
                [2 ]Department of Infectious Disease, Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai 264000, Shandong, People’s Republic of China
                Author notes
                Correspondence: Zenghui PuDepartment of Infectious Disease, Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai264000, Shandong, People’s Republic of ChinaTel +86 1 861 505 6980Email 18615056980@163.com

                These authors contributed equally to this work

                © 2019 Zhao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 20 June 2019
                : 02 August 2019
                Page count
                Figures: 5, References: 43, Pages: 11
                Original Research

                Pharmacology & Pharmaceutical medicine
                bone marrow mesenchymal stem cells,exosomes,d-galn/lps,apoptosis,autophagy,acute liver failure


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