76 results on '"Hui Qian"'
Search Results
2. Pretreatments with injured microenvironmental signals altered the characteristics of human umbilical cord mesenchymal stem cells.
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Cao H, Hui Q, Yan Y, Zhang C, Yang X, Ge L, and Xu W
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- Actins metabolism, Acute Kidney Injury therapy, Animals, Cell Hypoxia, Cell Proliferation, Cells, Cultured, Coculture Techniques, Female, Gene Expression Regulation drug effects, Hepatocyte Growth Factor metabolism, Humans, In Vitro Techniques, Insulin-Like Growth Factor I metabolism, Mesenchymal Stem Cells cytology, Pregnancy, Rats, Thy-1 Antigens metabolism, Culture Media pharmacology, Epithelial Cells cytology, Kidney Tubules cytology, Mesenchymal Stem Cells drug effects, Umbilical Cord cytology
- Abstract
Objective: Human umbilical cord mesenchymal stem cells (hUCMSCs) have renoprotective effects but the influence of the microenvironment on characteristics of hUCMSCs has not been well studied. Here, we investigate the effects of injury conditions on properties of hUCMSCs., Results: hUCMSCs were treated in vitro under conditions mimicking the injury microenvironment of acute kidney injury. Cells stimulated with factor-treated medium proliferated slowly at first but quickly afterwards their morphology subsequently changed from spindle to stellate shape. Increased number of cells with strong expression of thymine-1 (Thy-1) or α-smooth muscle actin (α-SMA) was detected at 1 or 2 weeks after stimulation. Hepatocyte growth factor (HGF) level markedly increased after culture for 6 h under hypoxia condition. The expressions of HGF and insulin growth factor-1 (IGF-1) were significantly up-regulated from 0.22 ± 0.03 to 0.9 ± 0.02 and 0.07 ± 0.03 to 0.19 ± 0.01 in H/R-treated hUCMSCs respectively. Co-culture with injured renal tubular epithelial cells significantly promoted the expression of HGF (1.19 ± 0.21) and IGF-1 (0.24 ± 0.03) in hUCMSCs., Conclusion: The characteristics of hUCMSCs change in response to inured conditions, which may enhance the efficacy of stem cell therapy and provide novel strategies in maximizing biological and functional properties of hUCMSCs.
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- 2016
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3. Single-cell RNA transcriptomic reveal the mechanism of MSC derived small extracellular vesicles against DKD fibrosis
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Cheng Ji, Jiahui Zhang, Hui Shi, Binghai Chen, Wenrong Xu, Jianhua Jin, and Hui Qian
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Single-cell RNA sequencing ,Fibrosis-associated macrophages ,Mesangial ,Mesenchymal stem cells ,Extracellular vesicles ,Antifibrosis niche ,Biotechnology ,TP248.13-248.65 ,Medical technology ,R855-855.5 - Abstract
Abstract Diabetic kidney disease (DKD), a chronic kidney disease, is characterized by progressive fibrosis caused due to persistent hyperglycemia. The development of fibrosis in DKD determines the patient prognosis, but no particularly effective treatment. Here, small extracellular vesicles derived from mesenchymal stem cells (MSC-sEV) have been used to treat DKD fibrosis. Single-cell RNA sequencing was used to analyze 27,424 cells of the kidney, we have found that a novel fibrosis-associated TGF-β1 +Arg1+ macrophage subpopulation, which expanded and polarized in DKD and was noted to be profibrogenic. Additionally, Actin+Col4a5+ mesangial cells in DKD differentiated into myofibroblasts. Multilineage ligand-receptor and cell-communication analysis showed that fibrosis-associated macrophages activated the TGF-β1/Smad2/3/YAP signal axis, which promotes mesangial fibrosis-like change and accelerates renal fibrosis niche. Subsequently, the transcriptome sequencing and LC-MS/MS analysis indicated that MSC-sEV intervention could restore the levels of the kinase ubiquitin system in DKD and attenuate renal interstitial fibrosis via delivering CK1δ/β-TRCP to mediate YAP ubiquitination degradation in mesangial cells. Our findings demonstrate the unique cellular and molecular mechanisms of MSC-sEV in treating the DKD fibrosis niche at a single-cell level and provide a novel therapeutic strategy for renal fibrosis.
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- 2024
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4. Neutrophil membrane engineered HucMSC sEVs alleviate cisplatin-induced AKI by enhancing cellular uptake and targeting
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Peipei Wu, Yuting Tang, Can Jin, Min Wang, Linli Li, Zhong Liu, Hui Shi, Zixuan Sun, Xiaomei Hou, Wenya Chen, Wenrong Xu, and Hui Qian
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Mesenchymal stem cells ,Engineered sEVs ,Neutrophil membrane ,Antioxidant ,Acute kidney injury ,Biotechnology ,TP248.13-248.65 ,Medical technology ,R855-855.5 - Abstract
Abstract Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEVs) have been demonstrated as a therapeutic agent to prevent and treat cisplatin-induced acute kidney injury (AKI). However, hucMSC-sEVs still face many problems and challenges in the repair and treatment of tissue injury, including short circulation time, insufficient targeting, and low therapeutic efficacy. Therefore, we constructed engineered hybrid vesicles fused with nanovesicles derived from human neutrophil membranes and hucMSC-sEVs, named neutrophil membrane engineered hucMSC-sEVs (NEX). NEX significantly enhanced the targeting of hucMSC-sEVs to injured kidney tissues, improved the impaired renal function via reducing pro-inflammatory cytokines expression, promoted the proliferation of renal tissue cells, and inhibited renal cell apoptosis in vivo. In addition, NEX enhanced hucMSC-sEVs uptake by NRK52E cells, but inhibited its uptake by RAW264.7 cells. Moreover, administration of NEX reduced cellular oxidative stress and promoted proliferation of NRK52E cells treated with cisplatin in vitro. In summary, our findings indicate that this design of a universal approach enhances the targeting and therapeutic efficacy of hucMSC-sEVs in kidney tissue regeneration, and provides new evidence promoting its clinical application.
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- 2022
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5. Improved therapeutics of modified mesenchymal stem cells: an update
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Dickson Kofi Wiredu Ocansey, Bing Pei, Yongmin Yan, Hui Qian, Xu Zhang, Wenrong Xu, and Fei Mao
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Mesenchymal stem cells ,Modification ,Genetic ,Preconditioning ,Therapy ,Medicine - Abstract
Abstract Background Mesenchymal stromal cells (MSCs) have attracted intense interest due to their powerful intrinsic properties of self-regeneration, immunomodulation and multi-potency, as well as being readily available and easy to isolate and culture. Notwithstanding, MSC based therapy suffers reduced efficacy due to several challenges which include unfavorable microenvironmental factors in vitro and in vivo. Body In the quest to circumvent these challenges, several modification techniques have been applied to the naïve MSC to improve its inherent therapeutic properties. These modification approaches can be broadly divided into two groups to include genetic modification and preconditioning modification (using drugs, growth factors and other molecules). This field has witnessed great progress and continues to gather interest and novelty. We review these innovative approaches in not only maintaining, but also enhancing the inherent biological activities and therapeutics of MSCs with respect to migration, homing to target site, adhesion, survival and reduced premature senescence. We discuss the application of the improved modified MSC in some selected human diseases. Possible ways of yet better enhancing the therapeutic outcome and overcoming challenges of MSC modification in the future are also elaborated. Conclusion The importance of prosurvival and promigratory abilities of MSCs in their therapeutic applications can never be overemphasized. These abilities are maintained and even further enhanced via MSC modifications against the inhospitable microenvironment during culture and transplantation. This is a turning point in MSC-based therapy with promising preclinical studies and higher future prospect.
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- 2020
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6. Extracellular Vesicles: A New Frontier for Cardiac Repair
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Benshuai You, Yang Yang, Zixuan Zhou, Yongmin Yan, Leilei Zhang, Jianhua Jin, and Hui Qian
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extracellular vesicles ,heart disease ,mesenchymal stem cells ,targeted delivery ,Pharmacy and materia medica ,RS1-441 - Abstract
The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been used to treat diseases. Growing evidence indicates that EVs play a cardioprotective role in heart disease by activating beneficial signaling pathways. Multiple functional components of EVs and intracellular molecular mechanisms are involved in the process. To overcome the shortcomings of native EVs such as their heterogeneity and limited tropism, a series of engineering approaches has been developed to improve the therapeutic efficiency of EVs. In this review, we present an overview of the research and future directions for EVs-based cardiac therapies with an emphasis on EVs-mediated delivery of therapeutic agents. The advantages and limitations of various modification strategies are discussed, and possible opportunities for improvement are proposed. An in-depth understanding of the endogenous properties of EVs and EVs engineering strategies could lead to a promising cell-free therapy for cardiac repair.
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- 2022
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7. Tumor-Educated Neutrophils Activate Mesenchymal Stem Cells to Promote Gastric Cancer Growth and Metastasis
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Jiahui Zhang, Cheng Ji, Wei Li, Zheying Mao, Yinghong Shi, Hui Shi, Runbi Ji, Hui Qian, Wenrong Xu, and Xu Zhang
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neutrophils ,mesenchymal stem cells ,cancer-associated fibroblasts ,gastric cancer ,progression ,Biology (General) ,QH301-705.5 - Abstract
In response to tumor signals, mesenchymal stem cells (MSCs) are recruited to tumor sites and activated to promote tumor progression. Emerging evidences suggest that in addition to tumor cells, non-tumor cells in tumor microenvironment could also interact with MSCs to regulate their phenotype and function. However, the mechanism for MSCs regulation in gastric cancer has not been fully understood. In this study, we reported that tumor-educated neutrophils (TENs) induced the transformation of MSCs into cancer-associated fibroblasts (CAFs) which in turn remarkably facilitated gastric cancer growth and metastasis. Mechanistic study showed that TENs exerted their effects by secreting inflammatory factors including IL-17, IL-23 and TNF-α, which triggered the activation of AKT and p38 pathways in MSCs. Pre-treatment with neutralizing antibodies to these inflammatory factors or pathway inhibitors reversed TENs-induced transformation of MSCs to CAFs. Taken together, these data suggest that TENs promote gastric cancer progression through the regulation of MSCs/CAFs transformation.
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- 2020
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8. hucMSC-sEVs-Derived 14-3-3
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Siqi, Yin, Wanzhu, Liu, Cheng, Ji, Yuan, Zhu, Yunjie, Shan, Zixuan, Zhou, Wenya, Chen, Leilei, Zhang, Zixuan, Sun, Wenqin, Zhou, and Hui, Qian
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Blood Glucose ,Rats, Sprague-Dawley ,Extracellular Vesicles ,14-3-3 Proteins ,Autophagy ,Diabetes Mellitus ,Animals ,Humans ,Diabetic Nephropathies ,Mesenchymal Stem Cells ,YAP-Signaling Proteins ,Rats ,Umbilical Cord - Abstract
As nanoscale membranous vesicles, human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEVs) have attracted extensive attention in the field of tissue regeneration. Under the premise that the mechanisms of hucMSC-sEVs on the treatment of diabetic kidney disease (DKD) have not been revealed clearly, we constructed DKD rat model with success. After tail vein injection, hucMSC-sEVs effectively reduced blood glucose, maintained body weight and improved renal function in DKD rats. Notably, we found that hucMSC-sEVs suppressed YAP expression in renal cortical regions. Further in vitro experiments, we confirmed that the expression of YAP in the nucleus of renal podocytes was increased, and the level of autophagy was inhibited in the high-glucose environment, which could be reversed by intervention with hucMSC-sEVs. We screened out the key protein 14-3-3
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- 2022
9. HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis
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Youwen Tan, Yan Huang, Rong Mei, Fei Mao, Dakai Yang, Jinwen Liu, Wenrong Xu, Hui Qian, and Yongmin Yan
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Liver Cirrhosis ,Cancer Research ,Immunology ,Mesenchymal Stem Cells ,Cell Biology ,Exosomes ,Phospholipid Hydroperoxide Glutathione Peroxidase ,Mice ,Cellular and Molecular Neuroscience ,Hepatic Stellate Cells ,Animals ,Ferroptosis ,Humans ,Beclin-1 - Abstract
Activated hepatic stellate cells (HSCs) are significant in liver fibrosis. Our past investigations have shown that human umbilical cord mesenchymal stem cells (hucMSCs) and their secreted exosomes (MSC-ex) could alleviate liver fibrosis via restraining HSCs activation. However, the mechanisms underlying the efficacy were not clear. Ferroptosis is a regulatory cell death caused by excessive lipid peroxidation, and it plays a vital role in the occurrence and development of liver fibrosis. In the present study, we aimed to study the proferroptosis effect and mechanism of MSC-ex in HSCs. MSC-ex were collected and purified from human umbilical cord MSCs. Proferroptosis effect of MSC-ex was examined in HSCs line LX-2 and CCl4 induced liver fibrosis in mice. Gene knockdown or overexpression approaches were used to investigate the biofactors in MSC-ex-mediated ferroptosis regulation. Results: MSC-ex could trigger HSCs ferroptosis by promoting ferroptosis-like cell death, ROS formation, mitochondrial dysfunction, Fe2+ release, and lipid peroxidation in human HSCs line LX-2. Glutathione peroxidase 4 (GPX4) is a crucial regulator of ferroptosis. We found that intravenous injection of MSC-ex significantly decreased glutathione peroxidase 4 (GPX4) expression in activated HSCs and collagen deposition in experimental mouse fibrotic livers. Mechanistically, MSC-ex derived BECN1 promoted HSCs ferroptosis by suppressing xCT-driven GPX4 expression. In addition, ferritinophagy and necroptosis might also play a role in MSC-ex-promoted LX-2 cell death. Knockdown of BECN1 in MSC diminished proferroptosis and anti-fibrosis effects of MSC-ex in LX-2 and fibrotic livers. MSC-ex may promote xCT/GPX4 mediated HSCs ferroptosis through the delivery of BECN1 and highlights BECN1 as a potential biofactor for alleviating liver fibrosis.
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- 2022
10. Mesenchymal stem cells-derived small extracellular vesicles alleviate diabetic retinopathy by delivering NEDD4
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Fengtian Sun, Yuntong Sun, Junyan Zhu, Xiaoling Wang, Cheng Ji, Jiahui Zhang, Shenyuan Chen, Yifan Yu, Wenrong Xu, and Hui Qian
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Extracellular Vesicles ,Diabetic Retinopathy ,NF-E2-Related Factor 2 ,Nedd4 Ubiquitin Protein Ligases ,Molecular Medicine ,Medicine (miscellaneous) ,Animals ,Mesenchymal Stem Cells ,Cell Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Proto-Oncogene Proteins c-akt ,Diabetes Mellitus, Experimental ,Rats - Abstract
Background As a leading cause of vision decline and severe blindness in adults, diabetic retinopathy (DR) is characterized by the aggravation of retinal oxidative stress and apoptosis in the early stage. Emerging studies reveal that mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) treatment represents a promising cell-free approach to alleviate ocular disorders. However, the repairing effects of MSC-sEV in DR remain largely unclear. This study aimed at exploring the role and the underlying mechanism of MSC-sEV in hyperglycemia-induced retinal degeneration. Methods In vivo, we used streptozotocin (STZ) to establish diabetic rat model, followed by the intravitreal injection of MSC-sEV to determine the curative effect. The cell viability and antioxidant capacity of retinal pigment epithelium (RPE) cells stimulated with high-glucose (HG) medium after MSC-sEV treatment were analyzed in vitro. By detecting the response of cell signaling pathways in MSC-sEV-treated RPE cells, we explored the functional mechanism of MSC-sEV. Mass spectrometry was performed to reveal the bioactive protein which mediated the role of MSC-sEV. Results The intravitreal injection of MSC-sEV elicited antioxidant effects and counteracted retinal apoptosis in STZ-induced DR rat model. MSC-sEV treatment also reduced the oxidative level and enhanced the proliferation ability of RPE cells cultured in HG conditions in vitro. Further studies showed that the increased level of phosphatase and tensin homolog (PTEN) inhibited AKT phosphorylation and nuclear factor erythroid 2-related factor 2 (NRF2) expression in RPE cells stimulated with HG medium, which could be reversed by MSC-sEV intervention. Through mass spectrometry, we illustrated that MSC-sEV-delivered neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) could cause PTEN ubiquitination and degradation, activate AKT signaling and upregulate NRF2 level to prevent DR progress. Moreover, NEDD4 knockdown impaired MSC-sEV-mediated retinal therapeutic effects. Conclusions Our findings indicated that MSC-sEV ameliorated DR through NEDD4-induced regulation on PTEN/AKT/NRF2 signaling pathway, thus revealing the efficiency and mechanism of MSC-sEV-based retinal protection and providing new insights into the treatment of DR.
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- 2021
11. hucMSCs Attenuate IBD through Releasing miR148b-5p to Inhibit the Expression of 15-lox-1 in Macrophages
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Jingjing Kang, Yongmin Yan, Hui Qian, Wenrong Xu, Zhaoyang Zhang, Gaoying Wang, Fei Mao, Jingyan Wang, and Xu Zhang
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Article Subject ,Blotting, Western ,Immunology ,Fluorescent Antibody Technique ,Real-Time Polymerase Chain Reaction ,Inflammatory bowel disease ,Mice ,lcsh:Pathology ,medicine ,Animals ,Arachidonate 15-Lipoxygenase ,Humans ,Macrophage ,Lipoxygenase Inhibitors ,Colitis ,RAW 264.7 Cells ,business.industry ,Macrophages ,Dextran Sulfate ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Transfection ,Inflammatory Bowel Diseases ,medicine.disease ,Blot ,Real-time polymerase chain reaction ,Cancer research ,business ,Research Article ,lcsh:RB1-214 - Abstract
Mesenchymal stem cells (MSCs) exert powerful immunosuppression in inflammatory bowel disease (IBD). Macrophages are the dominant inflammatory cells in enteritis regulated via MSCs. However, the roles of macrophages in the process of MSCs attenuating IBD and the mechanisms of MSCs regulating macrophages are largely unknown. In this study, DSS- (dextran sulfate sodium salt-) induced IBD in macrophage-depleted models of CD11b-DTR mice was used to study the relationship between hucMSCs (human umbilical cord mesenchymal stromal cells) and macrophage. Body weights, disease activities, and pathological changes were documented to assess the therapeutic effects of hucMSCs. Furthermore, hucMSCs transfected with miR148b-5p mimics and miR148b-5p inhibitors were cocultured with LPS-induced RAW264.7 cells to investigate the role of miR148b-5p in hucMSC-regulated colitis. The outcome indicated that hucMSCs attenuated the IBD by downregulating 15-lox-1 expression in macrophages. Further findings pointed out that hucMSCs transfected with miR148b-5p mimics could be elevated to promote the tissue repair and inhibit the expression of 15-lox-1 but failed to perform the function of easing enteritis when treated with miR148b-5p inhibitors. In conclusions, we propose that hucMSCs attenuate IBD by releasing miR148b-5p to inhibit the expression of 15-lox-1 in macrophages.
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- 2019
12. Systematic Exposition of Mesenchymal Stem Cell for Inflammatory Bowel Disease and Its Associated Colorectal Cancer
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Li Zhang, Fei Mao, Xiangyu Ma, Xu Zhang, Yanhui Yang, Yongmin Yan, Xiao Luo, Wenrong Xu, Hui Qian, Jingjing Kang, and Gaoying Wang
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0301 basic medicine ,Colorectal cancer ,medicine.medical_treatment ,lcsh:Medicine ,Inflammation ,Review Article ,Mesenchymal Stem Cell Transplantation ,Bioinformatics ,Inflammatory bowel disease ,General Biochemistry, Genetics and Molecular Biology ,Immunomodulation ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Humans ,Immunosuppression Therapy ,General Immunology and Microbiology ,business.industry ,lcsh:R ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Immunosuppression ,General Medicine ,Inflammatory Bowel Diseases ,medicine.disease ,digestive system diseases ,Microvesicles ,Clinical trial ,030104 developmental biology ,medicine.symptom ,Colorectal Neoplasms ,business - Abstract
Mesenchymal stem cells (MSCs) therapy has been applied to a wide range of diseases with excessive immune response, including inflammatory bowel disease (IBD), owing to its powerful immunosuppression and its ability to repair tissue lesions. Different sources of MSCs show different therapeutic properties. Engineering managements are able to enhance the immunomodulation function and the survival of MSCs involved in IBD. The therapeutic mechanism of MSCs in IBD mainly focuses on cell-to-cell contact and paracrine actions. One of the promising therapeutic options for IBD can focus on exosomes of MSCs. MSCs hold promise for the treatment of IBD-associated colorectal cancer because of their tumor-homing function and chronic inflammation inhibition. Encouraging results have been obtained from clinical trials in IBD and potential challenges caused by MSCs therapy are getting solved. This review can assist investigators better to understand the research progress for enhancing the efficacy of MSCs therapy involved in IBD and CAC.
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- 2018
13. Small extracellular vesicles derived from mesenchymal stem cell facilitate functional recovery in spinal cord injury by activating neural stem cells via the ERK1/2 pathway.
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Xinyuan Hu, Zhong Liu, Xinru Zhou, Qian Jin, Wenrong Xu, Xiao Zhai, Qiang Fu, and Hui Qian
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MESENCHYMAL stem cells ,EXTRACELLULAR vesicles ,SPINAL cord injuries ,CENTRAL nervous system diseases ,ENZYME-linked immunosorbent assay - Abstract
Spinal cord injury (SCI) causes severe neurological dysfunction leading to a devastating disease of the central nervous system that is associated with high rates of disability and mortality. Small extracellular vesicles (sEVs) derived from human umbilical cord mesenchymal stem cells (hucMSC-sEVs) have been explored as a promising strategy for treating SCI. In this study, we investigated the therapeutic effects of the intralesional administration of hucMSC-sEVs after SCI and determined the potential mechanisms of successful repair by hucMSC-sEVs. In vivo, we established the rat model of SCI. The Basso, Beattie, Bresnahan (BBB) scores showed that hucMSC-sEVs dramatically promoted the recovery of spinal cord function. The results of the hematoxylin-- eosin (HE) staining, Enzyme-Linked Immunosorbent Assay (ELISA), and immunohistochemistry showed that hucMSC-sEVs inhibited inflammation and the activation of glia, and promoted neurogenesis. Furthermore, we studied the effect of hucMSC-sEVs on neural stem cells(NSCs) in vitro. We found that hucMSC-sEVs did not improve the migration ability of NSCs, but promoted NSCs to proliferate and differentiate via the ERK1/2 signaling pathway. Collectively, these findings suggested that hucMSC-sEVs promoted the functional recovery of SCI by activating neural stem cells via the ERK1/2 pathway and may provide a new perspective and therapeutic strategy for the clinical application of hucMSC-sEVs in SCI treatment. [ABSTRACT FROM AUTHOR]
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- 2022
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14. HucMSC exosome-delivered 14-3-3ζ alleviates ultraviolet radiation-induced photodamage via SIRT1 pathway modulation
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Peipei Wu, Bin Zhang, Zixuan Sun, Xinru Zhou, Hui Qian, Yaoxiang Sun, Wenrong Xu, Xinye Han, Qian Jin, Peiwen Fu, and Linli Li
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Aging ,DNA damage ,Ultraviolet Rays ,exosomes ,medicine.disease_cause ,Exosome ,Umbilical Cord ,SIRT1 ,Western blot ,Sirtuin 1 ,In vivo ,medicine ,Autophagy ,Animals ,HaCaT Cells ,Humans ,Skin ,mesenchymal stem cells ,biology ,medicine.diagnostic_test ,Chemistry ,Cell Biology ,Hydrogen Peroxide ,Cell biology ,Rats ,Skin Aging ,HaCaT ,Disease Models, Animal ,Oxidative Stress ,14-3-3 Proteins ,Apoptosis ,Gene Knockdown Techniques ,biology.protein ,Female ,Oxidative stress ,Signal Transduction ,Research Paper - Abstract
Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) are nano-sized membrane-bound vesicles that have been reported to facilitate skin regeneration and repair. However, the roles played by hucMSC-ex in ultraviolet (UV) radiation-induced skin photodamage and the underlying mechanisms remain unknown. To investigate the functions of hucMSC-ex in a rat model of acute skin photodamage, immunofluorescence and immunohistochemical staining, quantitative real-time-polymerase chain reaction (qRT-PCR), western blot, and gene silencing assays were performed. We found that the in vivo subcutaneous injection of hucMSC-ex elicited antioxidant and anti-inflammatory effects against UV radiation-induced DNA damage and apoptosis. Further studies showed that the sirtuin 1 (SIRT1) expression level in skin keratinocytes (HaCaT) decreased in a time- and dose-dependent manner under in vitro UV radiation induced-oxidative stress conditions, which could be reversed by treatment with hucMSC-ex. The activation of SIRT1 significantly attenuated UV- and H2O2-induced cytotoxic damage by inhibiting oxidative stress and promoting the activation of autophagy. Our study found that 14-3-3ζ protein, which was delivered by hucMSC-ex, exerted a cytoprotective function via the modulation of a SIRT1-dependent antioxidant pathway. Collectively, our findings indicated that hucMSC-ex might represent a new potential agent for preventing or treating UV radiation-induced skin photodamage and aging.
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- 2020
15. Exosomes derived from hucMSC attenuate renal fibrosis through CK1δ/β-TRCP-mediated YAP degradation
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Yuan Zhu, Fengtian Sun, Leilei Zhang, Hui Shi, Qiongni Wang, Siqi Yin, Jiahui Zhang, Xu Zhang, Cheng Ji, Yongmin Yan, Hui Qian, and Wenrong Xu
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0301 basic medicine ,Cancer Research ,Immunology ,Exosomes ,Kidney ,urologic and male genital diseases ,Article ,Umbilical Cord ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Ubiquitin ,Fibrosis ,medicine ,Renal fibrosis ,Obstructive nephropathy ,Animals ,Humans ,lcsh:QH573-671 ,Gene knockdown ,biology ,lcsh:Cytology ,Chemistry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,YAP-Signaling Proteins ,Cell Biology ,beta-Transducin Repeat-Containing Proteins ,medicine.disease ,Biomechanical Phenomena ,Ubiquitin ligase ,Disease Models, Animal ,Mechanisms of disease ,030104 developmental biology ,medicine.anatomical_structure ,Casein Kinase Idelta ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Proteolysis ,biology.protein ,Cancer research ,Casein kinase 1 ,Apoptosis Regulatory Proteins ,Ureteral Obstruction - Abstract
Exosomes from human umbilical cord mesenchymal stem cells (hucMSC-Ex) have been suggested as novel nanomaterials for regenerative medicine. Here we explored the roles of hucMSC-Ex through regulating Yes-associated protein (YAP) in renal injury repair by using rat unilateral ureteral obstruction (UUO) models. Our study identified mechanical stress induced YAP nucleus expression and stimulated collagen deposition and interstitial fibrosis in the kidney. Then, infusion with hucMSC-Ex promoted YAP nuclear cytoplasmic shuttling and ameliorated renal fibrosis in UUO model. Interestingly, hucMSC-Ex delivered casein kinase 1δ (CK1δ) and E3 ubiquitin ligase β-TRCP to boost YAP ubiquitination and degradation. Knockdown of CK1δ and β-TRCP in hucMSC decreased the repairing effects of hucMSC-Ex on renal fibrosis. Our results suggest that hucMSC-Ex attenuates renal fibrosis through CK1δ/β-TRCP inhibited YAP activity, unveiling a new mechanism for the therapeutic effects of hucMSC-Ex on tissue injury and offering a potential approach for renal fibrosis treatment.
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- 2020
16. A novel method to isolate mesenchymal stem cells from mouse umbilical cord
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Fei Mao, Juanjuan Wang, Jie Zhang, Yongmin Yan, Hui Shi, Wenrong Xu, Hui Qian, Xu Zhang, and Bin Zhang
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0301 basic medicine ,Male ,Cancer Research ,Cellular differentiation ,Cell Separation ,Biology ,Stem cell marker ,Biochemistry ,Flow cytometry ,Immunophenotyping ,Umbilical Cord ,03 medical and health sciences ,Mice ,Immune system ,Toll-like receptor ,Antigens, CD ,Genetics ,medicine ,Animals ,Molecular Biology ,mouse ,Cells, Cultured ,Cell Proliferation ,mesenchymal stem cells ,medicine.diagnostic_test ,Mesenchymal stem cell ,Cell Differentiation ,Articles ,Flow Cytometry ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Oncology ,Immunology ,Molecular Medicine ,Cytokines ,Female ,Bone marrow ,Inflammation Mediators ,Biomarkers - Abstract
Mesenchymal stem cells (MSCs), derived from various tissues, are considered an ideal cell source for clinical use, among which MSCs from the umbilical cord exhibit advantages over those from adult tissues. In preclinical studies, mouse models and xenogeneic MSC treatment are most commonly used to imitate diseases and clinical practice, respectively. However, the efficiency of cross‑species therapy remains controversial, making it difficult to elucidate the underlying mechanisms. Thus, allogeneic therapy may be more instructive and meaningful in clinical use. To confirm this hypothesis, the present study established a novel method for the isolation and expansion of MSCs from mouse umbilical cords (mUC‑MSCs) to support in vivo experiments in mice. MSCs were isolated from mUCs and mouse bone marrow (mBM), and then identified by flow cytometry. The differences in mUC‑MSCs and mBM‑MSCs were analyzed using a growth curve and their differentiation ability. The results showed that the harvested cells exhibited general characteristics of MSCs and possessed the capacity for long‑term culture. Despite having similar morphology and surface antigens to MSCs derived from mouse bone marrow, the mUC‑MSCs showed differences in purification, proliferation, stem cell markers and differentiation. In addition to detailed characterization, the present study verified the presence of Toll‑like receptor 3 (TLR3), an important component of immune responses, in mUC‑MSCs. It was found that the activation of TLR3 upregulated the levels of stemness‑related proteins, and enhanced the secretion and mRNA levels of inflammatory cytokines in the pre‑treated mUC‑MSCs. Collectively, the results of the present study provide further insight into the features of newly established mUC‑MSCs, providing novel evidence for the selection of murine MSCs and their responses to TLR3 priming.
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- 2017
17. UBR2 Enriched in p53 Deficient Mouse Bone Marrow Mesenchymal Stem Cell-Exosome Promoted Gastric Cancer Progression via Wnt/β-Catenin Pathway
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Hailong Fu, Zhaofeng Liang, Jiahui Mao, Yongmin Yan, Xia Li, Hui Qian, Wenrong Xu, Xu Zhang, Huan Yang, and Bin Zhang
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0301 basic medicine ,Homeobox protein NANOG ,Ubiquitin-Protein Ligases ,Exosomes ,Exosome ,Mice ,03 medical and health sciences ,Stomach Neoplasms ,Cell Line, Tumor ,Animals ,Humans ,Wnt Signaling Pathway ,beta Catenin ,Cell Proliferation ,Tumor microenvironment ,biology ,CD44 ,Mesenchymal stem cell ,Wnt signaling pathway ,Cell Differentiation ,Mesenchymal Stem Cells ,LRP5 ,Cell Biology ,030104 developmental biology ,Disease Progression ,Cancer research ,biology.protein ,Molecular Medicine ,Stem cell ,Developmental Biology - Abstract
The deficiency or mutation of p53 has been linked to several types of cancers. The mesenchymal stem cell (MSC) is an important component in the tumor microenvironment, and exosomes secreted by MSCs can transfer bioactive molecules, including proteins and nucleic acid, to other cells in the tumor microenvironment to influence the progress of a tumor. However, whether the state of p53 in MSCs can impact the bioactive molecule secretion of exosomes to promote cancer progression and the regulatory mechanism remains elusive. Our study aimed to investigate the regulation of ubiquitin protein ligase E3 component n-recognin 2 (UBR2) enriched in exosomes secreted by p53 deficient mouse bone marrow MSC (p53–/–mBMMSC) in gastric cancer progression in vivo and in vitro. We found that the concentration of exosome was significantly higher in p53–/–mBMMSC than that in p53 wild-type mBMMSC (p53+/+mBMMSC). In particular, UBR2 was highly expressed in p53–/–mBMMSC cells and exosomes. P53–/–mBMMSC exosomes enriched UBR2 could be internalized into p53+/+mBMMSC and murine foregastric carcinoma (MFC) cells and induce the overexpression of UBR2 in these cells which elevated cell proliferation, migration, and the expression of stemness-related genes. Mechanistically, the downregulation of UBR2 in p53–/–mBMMSC exosomes could reverse these actions. Moreover, a majority of Wnt family members, β-catenin, and its downstream genes (CD44, CyclinD1, CyclinD3, and C-myc) were significantly decreased in MFC knockdown UBR2 and β-catenin depletion, an additional depletion of UBR2 had no significant difference in the expression of Nanog, OCT4, Vimentin, and E-cadherin. Taken together, our findings indicated that p53–/–mBMMSC exosomes could deliver UBR2 to target cells and promote gastric cancer growth and metastasis by regulating Wnt/β-catenin pathway.
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- 2017
18. miR-374 mediates the malignant transformation of gastric cancer-associated mesenchymal stem cells in an experimental rat model
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Jingyan Chen, Zhaofeng Liang, Hui Qian, Runbi Ji, Fei Mao, Hongbing Gu, Yongmin Yan, Zixun Sun, Wenrong Xu, and Xu Zhang
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0301 basic medicine ,Methylnitronitrosoguanidine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Cell ,Biology ,miR-374 ,Malignant transformation ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Stomach Neoplasms ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Cell Proliferation ,mesenchymal stem cells ,Tumor microenvironment ,Oncogene ,Interleukin-6 ,gastric cancer ,digestive, oral, and skin physiology ,Mesenchymal stem cell ,Articles ,General Medicine ,Cell cycle ,microenvironment ,Molecular medicine ,Rats ,Chemokine CXCL10 ,MicroRNAs ,Cell Transformation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Gastritis ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer research - Abstract
Mesenchymal stem cells (MSCs) are a critical component of the tumor microenvironment. Upon distinct pathological stimulus, MSCs show phenotypic and functional changes. Gastric cancer is one of the leading causes of cancer-related deaths worldwide. The roles and mechanisms of MSCs in gastric cancer have not been well characterized. In the present study, we investigated the roles of MSCs in the malignant transformation from gastritis to gastric cancer using an N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer model. We isolated MSCs from the gastric tissues of normal (RGN-MSCs) and MNNG-exposed rats (RGI-MSCs), and compared the biological properties of RGI-MSCs with RGN-MSCs. We found that RGI-MSCs had increased proliferative and migratory capabilities than these capacities noted in the RGN-MSCs. In addition, RGI-MSCs produced higher levels of IL-6, CXCL10 and MCP-1 than RGN-MSCs. Moreover, RGI-MSCs promoted the migration of normal gastric mucosa epithelial cells by inducing epithelial-mesenchymal transition (EMT). The upregulation of miR-374 in RGI-MSCs was partially responsible for their increased proliferative and migratory capabilities. Collectively, our findings provide new evidence for the roles of MSCs in gastric carcinogenesis, suggesting that targeting gastric cancer-associated MSCs may represent a novel avenue for gastric cancer therapy.
- Published
- 2017
19. Human umbilical cord mesenchymal stem cell exosomes alleviate sepsis-associated acute kidney injury via regulating microRNA-146b expression
- Author
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Cheng Ji, Lei Yin, Xinru Zhou, Yuyan Hu, Rongxue Zhang, Siqi Yin, Jingyan Chen, Yuan Zhu, Wanzhu Liu, Qiongni Wang, Hui Qian, Wenrong Xu, and Yang Li
- Subjects
0106 biological sciences ,0301 basic medicine ,Male ,Bioengineering ,Pharmacology ,Exosomes ,01 natural sciences ,Applied Microbiology and Biotechnology ,Umbilical cord ,Blood Urea Nitrogen ,Cell Line ,Umbilical Cord ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,010608 biotechnology ,medicine ,Animals ,Humans ,Blood urea nitrogen ,Kidney ,Creatinine ,business.industry ,Mesenchymal stem cell ,Acute kidney injury ,Interleukin ,Mesenchymal Stem Cells ,General Medicine ,Acute Kidney Injury ,medicine.disease ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Interleukin-1 Receptor-Associated Kinases ,chemistry ,Gene Expression Regulation ,Cisplatin ,business ,Biotechnology - Abstract
Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Ex) are a promising tool for the repair of acute kidney injury (AKI) caused by cisplatin and ischemia/reperfusion. However, the roles of hucMSC-Ex in sepsis-associated AKI repair and its mechanism are largely unknown. Hence, we constructed a sepsis model through cecal ligation and puncture (CLP), testing the benefits of hucMSC-Ex in the sepsis in terms of survival rate, serum renal markers levels, morphological changes and apoptosis. Immunohistochemistry staining and immunofluorescence assay were used to investigate the role of NF-κB activity in the repair of sepsis-associated AKI with hucMSC-Ex. HK-2 cells were transfected with microRNA-146b (miR-146b) mimics and inhibitors, respectively, and the regulatory effect of miR-146b on NF-κB activity was studied. We found that hucMSC-Ex treatment significantly decreased the serum creatinine (Cr) and blood urea nitrogen (BUN) levels, ameliorated the morphological damage and inhibited renal tubular cells apoptosis. More importantly, the survival rate at 72 h was 28% in CLP group and 45% in hucMSC-Ex group, respectively. Treatment with hucMSC-Ex improved survival in mice with sepsis. These effects of hucMSC-Ex were mediated by the inhibition of NF-κB activity and the lessening of pro-inflammatory response. Furthermore, hucMSC-Ex significantly increased miR-146b expression in kidney tissues. Conversely, interleukin (IL)-1 receptor-associated kinase (IRAK1) level, which is the target gene of miR-146b, clearly decreased in hucMSC-Ex group. In brief, this study showed that treatment with hucMSC-Ex decreased IRAK1 expression through the up-regulation of miR-146b level, led to the inhibition of NF-κB activity, and eventually alleviated sepsis-associated AKI and improved survival in mice with sepsis. HucMSC-Ex may be a novel therapeutic agent for the reduction of sepsis-associated AKI.
- Published
- 2019
20. Improved therapeutics of modified mesenchymal stem cells: an update
- Author
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Bing Pei, Fei Mao, Wenrong Xu, Yongmin Yan, Dickson Kofi Wiredu Ocansey, Hui Qian, and Xu Zhang
- Subjects
0301 basic medicine ,lcsh:Medicine ,Preconditioning ,Review ,Modification ,Mesenchymal Stem Cell Transplantation ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Genetic ,Medicine ,Humans ,Turning point ,business.industry ,lcsh:R ,Mesenchymal stem cell ,General Medicine ,Premature senescence ,Transplantation ,030104 developmental biology ,Target site ,030220 oncology & carcinogenesis ,Mesenchymal stem cells ,Therapy ,business ,Neuroscience ,Homing (hematopoietic) - Abstract
Background Mesenchymal stromal cells (MSCs) have attracted intense interest due to their powerful intrinsic properties of self-regeneration, immunomodulation and multi-potency, as well as being readily available and easy to isolate and culture. Notwithstanding, MSC based therapy suffers reduced efficacy due to several challenges which include unfavorable microenvironmental factors in vitro and in vivo. Body In the quest to circumvent these challenges, several modification techniques have been applied to the naïve MSC to improve its inherent therapeutic properties. These modification approaches can be broadly divided into two groups to include genetic modification and preconditioning modification (using drugs, growth factors and other molecules). This field has witnessed great progress and continues to gather interest and novelty. We review these innovative approaches in not only maintaining, but also enhancing the inherent biological activities and therapeutics of MSCs with respect to migration, homing to target site, adhesion, survival and reduced premature senescence. We discuss the application of the improved modified MSC in some selected human diseases. Possible ways of yet better enhancing the therapeutic outcome and overcoming challenges of MSC modification in the future are also elaborated. Conclusion The importance of prosurvival and promigratory abilities of MSCs in their therapeutic applications can never be overemphasized. These abilities are maintained and even further enhanced via MSC modifications against the inhospitable microenvironment during culture and transplantation. This is a turning point in MSC-based therapy with promising preclinical studies and higher future prospect.
- Published
- 2019
21. HucMSC Exosome-Delivered 14-3-3ζ Orchestrates Self-Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration
- Author
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Yongmin Yan, Zhaoji Pan, Hui Shi, Bin Zhang, Wenrong Xu, Yinghong Shi, Hailong Fu, Aihua Gong, Hui Qian, Xu Zhang, Wei Zhu, Huan Yang, and Mei Wang
- Subjects
0301 basic medicine ,Cell Count ,Protein Serine-Threonine Kinases ,Biology ,Exosomes ,Exosome ,Cell Line ,Substrate Specificity ,Umbilical Cord ,03 medical and health sciences ,WNT4 ,Serine ,Humans ,Regeneration ,Phosphorylation ,Wnt Signaling Pathway ,beta Catenin ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Skin ,Regeneration (biology) ,Mesenchymal stem cell ,Wnt signaling pathway ,Mesenchymal Stem Cells ,YAP-Signaling Proteins ,Cell Biology ,Anatomy ,Phosphoproteins ,Microvesicles ,Cell biology ,Wnt Proteins ,Protein Transport ,030104 developmental biology ,14-3-3 Proteins ,Molecular Medicine ,Collagen ,Stem cell ,Protein Binding ,Transcription Factors ,Developmental Biology - Abstract
Numerous studies showed that mesenchymal stem cells derived exosome (MSC-Ex) markedly enhanced tissue regeneration, however, the issue of whether MSC-Ex could control stem cells expansion after a regenerative response to prevent tissue from overcrowding and dysplasia remains to be established. Herein, we found that human umbilical cord MSC (hucMSC)-exosomal14-3-3ζ mediated the binding of YAP and p-LATS by forming a complex to promote the phosphorylation of YAP, which orchestrate exosomal Wnt4 signal in cutaneous regeneration. First, we assessed deep second-degree burn rats treated with hucMSC-Ex and discovered that hucMSC-Ex promoting self-regulation of Wnt/β-catenin signaling at the remodeling phase of cutaneous regeneration. HucMSC-Ex restricted excessive skin cell expansion and collagen deposition at 4 weeks. Under high cell density conditions, hucMSC-Ex inhibited Wnt/β-catenin signaling through induction of YAP phosphorylation. Second, hucMSC-Ex proteomic analysis revealed that 14-3-3 proteins could be transported by exosome. Using gain- and loss-of-function studies, our results showed that hucMSC-exosomal 14-3-3ζ controlled YAP activities and phosphorylation at Ser127 site, and were required for the binding of YAP and p-LATS. Further studies revealed that 14-3-3ζ recruited YAP and p-LATS to form a complex under high cells density status and 14-3-3ζ other than YAP or p-LATS was the key regulatory molecule of this complex. These findings collectively indicate that hucMSC-Ex functions not only as an “accelerator” of the Wnt/β-catenin signal to repair damaged skin tissue but also as a “brake” of the signal by modulating YAP to orchestrate controlled cutaneous regeneration.
- Published
- 2016
22. miR-155-5p inhibition promotes the transition of bone marrow mesenchymal stem cells to gastric cancer tissue derived MSC-like cells via NF-κB p65 activation
- Author
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Yiqing Tian, Mengchu Zhu, Huan Yang, Hui Qian, Wenrong Xu, Fang Yang, Wei Zhu, Jie Cai, Fei Mao, Hailong Fu, and Mei Wang
- Subjects
0301 basic medicine ,Pyrrolidines ,Stromal cell ,Transplantation, Heterologous ,Down-Regulation ,Mice, Nude ,Bone Marrow Cells ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Stomach Neoplasms ,Thiocarbamates ,Cell Line, Tumor ,medicine ,Animals ,Humans ,tumor microenvironment ,IKBKE ,3' Untranslated Regions ,Cells, Cultured ,Mice, Inbred BALB C ,mesenchymal stem cells ,Tumor microenvironment ,microRNA ,gastric cancer ,HEK 293 cells ,Mesenchymal stem cell ,Transcription Factor RelA ,Cancer ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Cell Transformation, Neoplastic ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,RNA Interference ,Bone marrow ,Research Paper - Abstract
Gastric cancer tissue-derived MSC-like cells (GC-MSC) share similar characteristics to bone marrow MSC (BM-MSC); however, the phenotypical and functional differences and the molecular mechanism of transition between the two cell types remain unclear. Compared to BM-MSC, GC-MSC exhibited the classic phenotype of reactive stroma cells, a stronger gastric cancer promoting capacity and lower expression of miR-155-5p. Inhibition of miR-155-5p by transfecting miRNA inhibitor induced a phenotypical and functional transition of BM-MSC into GC-MSC-like cells, and the reverse experiment deprived GC-MSC of tumor-promoting phenotype and function. NF-kappa B p65 (NF-κB p65) and inhibitor of NF-kappa B kinase subunit epsilon (IKBKE/IKKε) were identified as targets of miR-155-5p and important for miRNA inhibitor activating NF-κB p65 in the transition. Inactivation of NF-κB by pyrrolidine dithiocarbamic acid (PDTC) significantly blocked the effect of miR-155-5p inhibitor on BM-MSC. IKBKE, NF-κB p65 and phospho-NF-κB p65 proteins were highly enriched in MSC-like cells of gastric cancer tissues, and the latter two were correlated with the pathological progression of gastric cancer. In GC-MSC, the expression of miR-155-5p was downregulated and NF-κB p65 protein was increased and activated. NF-κB inactivation by PDTC or knockdown of its downstream cytokines reversed the phenotype and function of GC-MSC. Taken together, our findings revealed that miR-155-5p downregulation induces BM-MSC to acquire a GC-MSC-like phenotype and function depending on NF-κB p65 activation, which suggests a novel mechanism underlying the cancer associated MSC remodeling in the tumor microenvironment and offers an effective target and approach for gastric cancer therapy.
- Published
- 2016
23. Mesenchymal stem cell-derived extracellular vesicles: a new impetus of promoting angiogenesis in tissue regeneration
- Author
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Bin Zhang, Yinghong Shi, Adnan Nomi, Hui Shi, Zhang Lei-lei, and Hui Qian
- Subjects
0301 basic medicine ,Cancer Research ,Cell signaling ,Angiogenesis ,Immunology ,Myocardial Infarction ,Neovascularization, Physiologic ,Cell Communication ,Biology ,Regenerative Medicine ,Extracellular vesicles ,Regenerative medicine ,Brain Ischemia ,Neovascularization ,03 medical and health sciences ,Extracellular Vesicles ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Animals ,Humans ,Regeneration ,Genetics (clinical) ,Transplantation ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Cell biology ,Stroke ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,medicine.symptom ,Biogenesis - Abstract
Over the past few decades, extracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication. EVs encapsulate and convey information to surrounding cells or distant cells, where they mediate cellular biological responses. Among their multifaceted roles in the modulation of biological responses, the involvement of EVs in vascular development, growth and maturation has been widely documented and their potential therapeutic application in regenerative medicine or in the treatment of angiogenesis-related diseases is drawing increasing interest. In this review, we have summarized the details about the current knowledge on biogenesis of EVs and conventional isolation methods. Evidence supporting the use of EVs derived from mesenchymal stromal cells (MSCs) to enhance angiogenesis in the development of insufficient angiogenesis, such as chronic wounds, stroke and myocardial infarction, will also be discussed critically. Finally, the main challenges and prerequisites for their therapeutic applications will be evaluated.
- Published
- 2018
24. Resveratrol improves human umbilical cord-derived mesenchymal stem cells repair for cisplatin-induced acute kidney injury
- Author
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Cheng Ji, Rongxue Zhang, Lei Yin, Jingyan Chen, Peipei Wu, Leilei Zhang, Hui Qian, Wenrong Xu, Yaoxiang Sun, Hui Shi, and Bin Zhang
- Subjects
0301 basic medicine ,CD31 ,Cancer Research ,Angiogenesis ,Immunology ,Fluorescent Antibody Technique ,Resveratrol ,Cell Line ,Umbilical Cord ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Paracrine signalling ,Cell Movement ,In Situ Nick-End Labeling ,Medicine ,Animals ,Humans ,lcsh:QH573-671 ,Kidney ,business.industry ,lcsh:Cytology ,Mesenchymal stem cell ,Acute kidney injury ,Mesenchymal Stem Cells ,Cell Biology ,Acute Kidney Injury ,medicine.disease ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Cell culture ,Cancer research ,Female ,Cisplatin ,business ,Signal Transduction - Abstract
Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are a promising tool for damaged tissues repair, especially for the kidney. However, their efficacy requires improvement. In order to optimize the clinical utility of hucMSCs, we adopted a strategy of treating hucMSCs with 20 μmol/L of resveratrol (Res-hucMSCs), applying it in a cisplatin-induced acute kidney injury model. Interestingly, we found that Res-hucMSCs exhibited a more efficient repairing effect than did hucMSCs. Resveratrol-promoted hucMSCs secreted platelet-derived growth factor-DD (PDGF-DD) into renal tubular cells resulting in downstream phosphorylation of extracellular signal-regulated kinase (ERK), which inhibited renal tubular cells apoptosis. In contrast, PDGF-DD knockdown impaired the renal protection of Res-hucMSCs. In addition, angiogenesis induced by PDGF-DD in endothelial cells was also involved in the renal protection of Res-hucMSCs. The conditioned medium of Res-hucMSCs accelerated proliferation and migration of vascular endothelial cells in vitro and CD31 was in a high-level expression in Res-hucMSCs group in vivo. Nevertheless, the angiogenesis was abrogated when Res-hucMSCs were treated with PDGF-DD siRNA. In conclusion, our findings showed that resveratrol-modified hucMSCs activated ERK pathway in renal tubular cells and promoted angiogenesis in endothelial cells via paracrine PDGF-DD, which could be a novel strategy for enhancing the therapy efficacy of hucMSCs in cisplatin-induced kidney injury.
- Published
- 2018
25. HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing
- Author
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Wei Zhu, Wenrong Xu, Hui Qian, Yanhua Zhu, Lijun Wu, Xu Zhang, Bin Zhang, Mei Wang, Xiaodan Wu, Aihua Gong, and Hui Shi
- Subjects
Wound Healing ,Mesenchymal stem cell ,Wnt signaling pathway ,Mesenchymal Stem Cells ,Cell Biology ,Biology ,Exosomes ,Exosome ,Rats ,Cell biology ,Wnt4 Protein ,In vivo ,Immunology ,Animals ,Humans ,Molecular Medicine ,Stem cell ,Wound healing ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Signal Transduction ,Skin ,Developmental Biology - Abstract
Mesenchymal stem cell-derived exosomes (MSC-Ex) play important roles in tissue injury repair, however, the roles of MSC-Ex in skin damage repair and its mechanisms are largely unknown. Herein, we examined the benefit of human umbilical cord MSC-derived exosome (hucMSC-Ex) in cutaneous wound healing using a rat skin burn model. We found that hucMSC-Ex-treated wounds exhibited significantly accelerated re-epithelialization, with increased expression of CK19, PCNA, collagen I (compared to collagen III) in vivo. HucMSC-Ex promoted proliferation and inhibited apoptosis of skin cells after heat-stress in vitro. We also discovered that Wnt4 was contained in hucMSC-Ex, and hucMSC-Ex-derived Wnt4 promoted β-catenin nuclear translocation and activity to enhance proliferation and migration of skin cells, which could be reversed by β-catenin inhibitor ICG001. In vivo studies confirmed that the activation of Wnt/β-catenin by hucMSC-Ex played a key role in wound re-epithelialization and cell proliferation. Furthermore, knockdown of Wnt4 in hucMSC-Ex abrogated β-catenin activation and skin cell proliferation and migration in vitro. The in vivo therapeutic effects were also inhibited when the expression of Wnt4 in hucMSC-Ex was interfered. In addition, the activation of AKT pathway by hucMSC-Ex was associated with the reduction of heat stress-induced apoptosis in rat skin burn model. Collectively, our findings indicate that exosome-delivered Wnt4 provides new aspects for the therapeutic strategy of MSCs in cutaneous wound healing. Stem Cells 2015;33:2158–2168
- Published
- 2015
26. Extracellular regulated protein kinases 1/2 phosphorylation is required for hepatic differentiation of human umbilical cord-derived mesenchymal stem cells
- Author
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Limin Li, Wenrong Xu, Bin Zhang, Hui Qian, Yuan Zhu, Yongmin Yan, Zixuan Sun, Feng Sun, Wei Zhu, and Wei Li
- Subjects
MAPK/ERK pathway ,Time Factors ,Cellular differentiation ,Biology ,Mitogen-activated protein kinase kinase ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Animals ,Cytochrome P-450 CYP3A ,Humans ,Urea ,Phosphorylation ,Protein kinase A ,Cells, Cultured ,Original Research ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase Kinases ,Mitogen-Activated Protein Kinase 3 ,Kinase ,Liver cell ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Fetal Blood ,Molecular biology ,Culture Media, Conditioned ,Hepatocytes ,raf Kinases ,Liver function ,Signal Transduction - Abstract
Mesenchymal stem cells (MSCs) have the capacity to restore liver function by differentiating into hepatocyte like cells. However, the underlying mechanisms are not well understood. Here, we have investigated the signals involved in the hepatic differentiation of human umbilical cord-derived mesenchymal stem cells (hUCMSCs). hUCMSCs were treated with mouse fetal liver-conditioned medium (FLCM) to induce hepatic differentiation. Flow cytometry, reverse transcription PCR, real-time PCR, immunocytochemistry, and polymerase chain reaction (PCR) array were used to detect the expression of MSC- and hepotocyte-specific markers in FLCM-treated hUCMSCs. Urea production and cytochrome P450 3A4 (CYP3A4) activity were used as indicators to evaluate liver cell characteristics. Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) was analyzed in hUCMSCs by Western blotting. Following FLCM treatment, expression of MSC-specific markers decreased, while hepatocyte-specific gene expression was increased. Urea production, albumin secretion, glycogen storage, and CYP3A4 activity were significantly enhanced in FLCM-treated cells. In addition, ERK1/2 phosphorylation was increased in a time-dependent manner through Raf/MEK/ERK pathway, and phosphorylation was sustained at a high level during hepatic induction. Inhibition of ERK1/2 activation by U0126 (an ERK1/2 inhibitor) and pFLAG-CMV-ERK1(K71R) (negative mutant of ERK1) reversed the expression of liver-specific genes in hUCMSCs and affected hepatic function significantly. In summary, this work shows that ERK1/2 phosphorylation plays an important role in inducing hepatic differentiation of hUCMSCs in FLCM.
- Published
- 2015
27. Pre-treatment of human umbilical cord-derived mesenchymal stem cells with interleukin-6 abolishes their growth-promoting effect on gastric cancer cells
- Author
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Wenrong Xu, Mengchu Zhu, Hui Qian, Xu Zhang, Mei Wang, Qiang Zhang, Tingting Yang, Feng Huang, and Jie Cai
- Subjects
Chemokine ,Stromal cell ,medicine.medical_treatment ,Mice, Nude ,Biology ,CCL5 ,Umbilical Cord ,Mice ,Cancer stem cell ,Stomach Neoplasms ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,human umbilical cord-derived mesenchymal stem cells ,Mice, Inbred BALB C ,Interleukin-6 ,gastric cancer ,Mesenchymal stem cell ,NF-kappa B ,Mesenchymal Stem Cells ,General Medicine ,Articles ,Actins ,Coculture Techniques ,Neoplasm Proteins ,Cytokine ,Immunology ,Cancer cell ,Cancer research ,biology.protein ,Heterografts ,Tumor necrosis factor alpha ,Neoplasm Transplantation - Abstract
The inflammatory microenvironment contributes to cancer development and progression. Mesenchymal stem cells (MSCs), as important stromal cells, may be 'educated' by the inflammatory microenvironment to support the development of gastric cancer. Cytokines are a key component of cancer-related inflammation. Interleukin (IL)-6, as an inflammatory cytokine, has multiple roles in cancer. However, whether MSCs can be 'educated' by IL-6 to support gastric cancer remains unknown. In the present study, we focused on the phenotype and function of human umbilical cord-derived MSCs hUC‑MSCs pre-treated with IL-6 in gastric cancer. We found that the protein levels of α-smooth muscle actin (α-SMA) were upregulated, and phosphorylated nuclear factor (NF)-κB protein levels were downregulated in the hUC‑MSCs pre-treated with IL-6, as shown by western blot analysis. The levels of tumor‑promoting cytokines, including chemokine (C-C motif) ligand 5 (CCL5), platelet-derived growth factor‑BB (PDGF‑BB), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α(TNFα), were markedly reduced in the hUC‑MSCs following treatment with IL-6, as shown by RT-qPCR. In in vitro experiments, we co-cultured MSCs with N-methyl‑N'‑nitro‑N‑nitrosoguanidine (MNNG)‑transformed GES-1 gastric epithelial cells or SGC-7901 gastric cancer cells. Transwell and colony-forming cell assays revealed that the hUC-MSCs significantly promoted gastric cellular migration and proliferation. However, following treatment with IL-6, the hUC-MSCs had no growth-promoting effect on the gastric epithelial cells and gastric cancer cells. In in vivo experiments, we co-transplanted MSCs and SGC-7901 cells into nude mice in order to establish a nude mouse model of gastric cancer. The hUC-MSCs significantly promoted the growth gastric tumors through the promotion of cell proliferation and the inhibition of cell apoptosis. On the contrary, pre-treatment with IL-6 provided the hUC‑MSCs with the ability to inhibit cell proliferation and significantly induce cell apoptosis. Taken together, our findings indicate that pre-treatment with IL-6 significantly abolishes the ability of hUC-MSCs to promote gastric epithelial cell proliferation and migration and provide new insight into the effects of the inflammatory cytokine, IL-6, on the tumor-promoting ability of MSCs and its role in gastric cancer.
- Published
- 2014
28. MSC-exosome: A novel cell-free therapy for cutaneous regeneration
- Author
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Hui Shi, Wenrong Xu, Hui Qian, Peipei Wu, and Bin Zhang
- Subjects
0301 basic medicine ,Chronic wound ,Cancer Research ,Angiogenesis ,Immunology ,Exosomes ,Exosome ,Extracellular matrix ,03 medical and health sciences ,Skin Physiological Phenomena ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Regeneration ,RNA, Messenger ,Genetics (clinical) ,Skin ,Transplantation ,Wound Healing ,Cell-Free System ,business.industry ,Regeneration (biology) ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Microvesicles ,Cell biology ,MicroRNAs ,030104 developmental biology ,Oncology ,medicine.symptom ,business ,Wound healing - Abstract
Cutaneous regeneration is a dynamic and complex process that requires a series of coordinated interactions involving epidermal cells, dermal cells, growth factors, the extracellular matrix (ECM), nerves and blood vessels at a damaged site. Mesenchymal stromal cells (MSCs) have been reported to participate in all afore-mentioned stages. Exosomes are one of the key secretory products of MSCs, resembling the effect of parental MSCs. They can shuttle various proteins, messenger RNA (mRNA) and microRNAs (miRNAs) to modulate the activity of recipient cells, and play important roles in cutaneous wound healing. Compared with MSCs, exosomes are more convenient to store and transport. Moreover, they avoid many risks associated with cell transplantation. Therefore, MSC-exosome-mediated therapy may be more safe and efficient. In this review, we summarize the latest studies and observations on the role of MSC-exosome in the acute and chronic wound model and provide a comprehensive understanding of the role of exosomes in wound healing. This review can assist investigators in exploring new therapeutic strategies for enhancing the efficacy of MSC-exosome for cutaneous repair and regeneration.
- Published
- 2017
29. YAP signaling in gastric cancer-derived mesenchymal stem cells is critical for its promoting role in cancer progression
- Author
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Zhaoji Pan, Yang Lunyu, Hui Shi, Zhaofeng Liang, Fei Mao, Bin Zhang, Wenrong Xu, Xu Zhang, Peipei Wu, Hui Qian, Rong Li, Benshuai You, and Yiqing Tian
- Subjects
0301 basic medicine ,Oncology ,Male ,Yes-associated protein 1 ,Cancer Research ,Cell Cycle Proteins ,medicine.disease_cause ,Mice ,0302 clinical medicine ,mesenchymal stem cell ,Tube formation ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,Nuclear Proteins ,Articles ,Middle Aged ,Endothelial stem cell ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Disease Progression ,Neoplastic Stem Cells ,Heterografts ,Female ,Signal Transduction ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Biology ,03 medical and health sciences ,Cancer stem cell ,Stomach Neoplasms ,Internal medicine ,medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Aged ,Cell Proliferation ,gastric cancer ,Mesenchymal stem cell ,Cancer ,Mesenchymal Stem Cells ,β-catenin ,medicine.disease ,030104 developmental biology ,Cancer cell ,Cancer research ,progression ,Carcinogenesis ,Transcription Factors - Abstract
Cancer-associated mesenchymal stem cells (MSCs) are critically involved in tumor development and progression. However, the mechanisms of action for MSCs in cancer remain largely unknown. Herein, we reported that the expression of Yes-associated protein 1 (YAP) was higher in gastric cancer derived mesenchymal stem cells (GC‑MSCs) than that in bone marrow derived MSCs (BM‑MSCs). YAP knockdown not only inhibited the growth, migration and invasion, and stemness of GC‑MSCs, but also suppressed their promoting effect on gastric cancer growth in vitro and in vivo. In addition, the interference of YAP expression in GC‑MSCs also attenuated the promoting role of gastric cancer cells in endothelial cell tube formation and migration. Mechanistically, YAP knockdown reduced the activation of β-catenin and its target genes in gastric cancer cells by GC‑MSCs. Taken together, these findings suggest that YAP activation in GC‑MSCs plays an important role in promoting gastric cancer progression, which may represent a potential target for gastric cancer therapy.
- Published
- 2017
30. Autophagy: A new treatment strategy for MSC-based therapy in acute kidney injury (Review)
- Author
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Juanjuan Wang, Yongmin Yan, Zhaofeng Liang, Wenrong Xu, Hui Qian, Haoyuan Jia, Nitin Tandra, and Bin Zhang
- Subjects
0301 basic medicine ,Cancer Research ,Programmed cell death ,urologic and male genital diseases ,Bioinformatics ,Mesenchymal Stem Cell Transplantation ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,Genetics ,Autophagy ,Medicine ,Animals ,Humans ,Molecular Biology ,urogenital system ,business.industry ,Adenine ,TOR Serine-Threonine Kinases ,Mesenchymal stem cell ,Acute kidney injury ,Cancer ,Mesenchymal Stem Cells ,Acute Kidney Injury ,medicine.disease ,Molecular medicine ,female genital diseases and pregnancy complications ,MicroRNAs ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Reperfusion Injury ,Molecular Medicine ,business ,Reperfusion injury - Abstract
Acute kidney injury (AKI) is a common and serious medical condition associated with poor health outcomes. Autophagy is a conserved multistep pathway that serves a major role in many biological processes and diseases. Recent studies have demonstrated that autophagy is induced in proximal tubular cells during AKI. Autophagy serves a pro‑survival or pro‑death role under certain conditions. Furthermore, mesenchymal stem cells (MSCs) have therapeutic potential in the repair of renal injury. This review summarizes the recent progress on the role of autophagy in AKI and MSCs‑based therapy for AKI. Further research is expected to prevent and treat acute kidney injury.
- Published
- 2017
31. HucMSC exosome-transported 14-3-3ζ prevents the injury of cisplatin to HK-2 cells by inducing autophagy in vitro
- Author
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Jing Yu, Fei Mao, Juanjuan Wang, Bin Zhang, Yongmin Yan, Haoyuan Jia, Xiao Xu, Cheng Ji, Lei Yin, Wenrong Xu, and Hui Qian
- Subjects
0301 basic medicine ,Cancer Research ,Stromal cell ,Immunology ,Exosomes ,Exosome ,Umbilical Cord ,03 medical and health sciences ,Western blot ,Autophagy ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Genetics (clinical) ,Cisplatin ,Transplantation ,biology ,medicine.diagnostic_test ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Proliferating cell nuclear antigen ,Rats ,030104 developmental biology ,HEK293 Cells ,Oncology ,Terminal deoxynucleotidyl transferase ,14-3-3 Proteins ,Apoptosis ,Gene Knockdown Techniques ,biology.protein ,Cancer research ,business ,medicine.drug - Abstract
Background aims On the basis of previous studies, exosomes secreted by human umbilical cord mesenchymal stromal cell (hucMSC-ex) could prevent and repair acute kidney injury induced by cisplatin in rats. However, its potential mechanism is still unclear. In the present study, the model with hucMSC-ex pretreated human renal tubular epithelial cell lines HK-2 that could prevent the injury of cisplatin was successfully established. Methods First, we pretreated the HK-2 cells with hucMSC-ex for 24 h. Cisplatin was then used to injure HK-2 cells. Gain and loss of function study were used to explore the role of 14-3-3ζ. The expression level of proliferating cell nuclear antigen (PCNA) was analyzed by immunofluorescence assay and Western blot. The number of apoptotic cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometry analysis. The formation of autophagosomes was observed under super-resolution optical microscope. Western blot was used to analyze the expression levels of LC3B, P62, 14-3-3ζ and Bax. Results Pretreating cells with hucMSC-ex could prevent the injury of cisplatin by reducing the number of apoptotic cells and increasing the expression level of PCNA. Simultaneously, the autophagic level was up-regulated. The application of autophagic inhibitor 3-methyladenine (3-MA) could reverse the protective effect of hucMSC-ex. The overexpression of 14-3-3ζ enhanced the autophagic level and protected the injury of cisplatin. The knock-down of 14-3-3ζ could reduce the autophagic level and enhance the disadvantage of cisplatin. The enhanced injury of cisplatin was reversed when the knock-down of 14-3-3ζ was replenished with hucMSC-ex. Conclusions 14-3-3ζ transported by hucMSC-ex may up-regulate autophagic level in HK-2 cells, which can prevent the injury of cisplatin. This discovery provides the new theoretical basis for the prevention of cisplatin-induced nephrotoxicity by hucMSC-ex.
- Published
- 2017
32. Human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease through the regulation of 15-LOX-1 in macrophages
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Fei Mao, Yunbing Wu, Xudong Tang, Juanjuan Wang, Hui Qian, Zhaoji Pan, Yongmin Yan, Wenrong Xu, Xu Zhang, Peng Zhang, and Bin Zhang
- Subjects
0301 basic medicine ,Male ,STAT3 Transcription Factor ,Colon ,Bioengineering ,Mesenchymal Stem Cell Transplantation ,digestive system ,Applied Microbiology and Biotechnology ,Umbilical cord ,Inflammatory bowel disease ,Regenerative medicine ,03 medical and health sciences ,Mice ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Arachidonate 15-Lipoxygenase ,Humans ,Dextran Sulfate Sodium ,STAT3 ,Gene ,biology ,Macrophages ,Mesenchymal stem cell ,Dextran Sulfate ,Mesenchymal Stem Cells ,General Medicine ,medicine.disease ,Inflammatory Bowel Diseases ,digestive system diseases ,In vitro ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,biology.protein ,Cancer research ,Cytokines ,Spleen ,Biotechnology ,Signal Transduction - Abstract
To investigate the role of human umbilical cord mesenchymal stem cells (hucMSCs) in the treatment of dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD). ICG-hucMSCs homed to colon tissues of IBD mice 12 h after injection. The injection of hucMSCs significantly relieved the IBD symptoms and inflammatory cell infiltration. The expression of IL-10 gene increased while those of 15-LOX-1, TNF-α, IL-6, IL-1β, and IP-10 genes decreased in colon tissues and spleens of hucMSCs-treated mice. The activation of STAT3 was inhibited in colon tissues and spleens of IBD mice that were treated with hucMSCs. In addition, the percentage of macrophages decreased in colon tissues and spleens of hucMSCs-treated IBD mice. Moreover, we provided evidence that in vitro co-culture with hucMSCs inhibited the expression of 15-LOX-1, IL-6 and p-STAT3 in mouse enterocoelia macrophages. HucMSCs alleviate DSS-induced IBD through the modulation of 15-LOX-1 in macrophages.
- Published
- 2017
33. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Inflammatory Bowel Disease in Mice
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Jingjing Kang, Fei Mao, Yongmin Yan, Hui Qian, Xudong Tang, Yunbing Wu, Wenrong Xu, Xu Zhang, and Bin Zhang
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Article Subject ,Colon ,lcsh:Medicine ,Exosomes ,Inflammatory bowel disease ,Exosome ,Umbilical cord ,General Biochemistry, Genetics and Molecular Biology ,Umbilical Cord ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Colitis ,General Immunology and Microbiology ,business.industry ,Macrophages ,Dextran Sulfate ,Mesenchymal stem cell ,lcsh:R ,Mesenchymal Stem Cells ,General Medicine ,Inflammatory Bowel Diseases ,medicine.disease ,In vitro ,Microvesicles ,digestive system diseases ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cytokines ,business ,Infiltration (medical) ,Research Article - Abstract
Exosomes secreted by mesenchymal stem cells (MSCs) have shown repairing effects on several tissue injury diseases. In this study, we aimed to investigate the effects of exosomes released from human umbilical cord mesenchymal stem cells (hucMSCs) on the treatment of dextran sulfate sodium- (DSS-) induced inflammatory bowel disease (IBD) and to explore the underlying mechanism. We found that indocyanine green (ICG) labeled exosomes homed to colon tissues of IBD mice at 12 hours after injection. Exosomes significantly relieved the severity of IBD in mice as hucMSCs. The expression of IL-10 gene was increased while that of TNF-α, IL-1β, IL-6, iNOS, and IL-7 genes was decreased in the colon tissues and spleens of exosomes-treated mice. Furthermore, the infiltration of macrophages into the colon tissues was decreased by exosome treatment in IBD mice. In addition, we provided evidence that in vitro coculture with exosomes inhibited the expression of iNOS and IL-7 in mouse enterocoelia macrophages. Moreover, we found that the expression of IL-7 was higher in the colon tissues of colitis patients than that of healthy controls. Our findings suggest that exosomes from hucMSCs have profound effects on alleviating DSS-induced IBD and may exert their impact through the modulation of IL-7 expression in macrophages.
- Published
- 2017
34. H. pylori infection-induced MSC differentiation into CAFs promotes epithelial-mesenchymal transition in gastric epithelial cells
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Hui Qian, Jie Cai, Qiang Zhang, Wenrong Xu, Feng Huang, Mei Wang, Tingting Yang, Xu Zhang, and Wei Zhu
- Subjects
Epithelial-Mesenchymal Transition ,Cell ,Chronic gastritis ,Apoptosis ,Inflammation ,Biology ,Cell Line ,Helicobacter Infections ,Colony-Forming Units Assay ,Stomach Neoplasms ,Genetics ,medicine ,Humans ,Epithelial–mesenchymal transition ,Fibroblast ,Cell Shape ,Cell Proliferation ,Helicobacter pylori ,Tumor Suppressor Proteins ,Stomach ,Mesenchymal stem cell ,Cell Differentiation ,Epithelial Cells ,Mesenchymal Stem Cells ,Cell migration ,General Medicine ,Fibroblasts ,Cell cycle ,medicine.disease ,medicine.anatomical_structure ,Culture Media, Conditioned ,Immunology ,Cancer research ,Cytokines ,medicine.symptom - Abstract
Mesenchymal stem cell (MSC) tropism to injured tissue sites in response to inflammation and wounds has been suggested. MSC activation and recruitment by Helicobacter pylori (H. pylori)-infected gastrointestinal epithelial cells has been demonstrated. As a component of the chronic gastritis microenvironment, MSCs play critical roles in the development of H. pylori-associated gastric mucosal lesions/malignancies. However, the mechanisms responsible for this process remain largely unknown. In this study, we demonstrate that H. pylori infection induces the differentiation of MSCs into cancer-associated fibroblast (CAF)-like cells. H. pylori-infected MSCs possessed an altered cytokine profile and induced epithelial-mesenchymal transition in gastric epithelial cells, leading to destroyed cell junctions, enhanced cell migration, reduced cell apoptosis and increased oncogenic potential. In conclusion, our findings indicate that H. pylori infection may cause gastric lesions/malignancies by inducing the differentiation of MSCs into CAFs and suggest a novel mechanism of action and role of MSCs in the development and progression of gastric cancer.
- Published
- 2013
35. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis
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Yongmin Yan, Li Shen, Ying Zhou, Xu Zhang, Tingfen Li, Wenrong Xu, Mei Wang, Hui Qian, Bingying Wang, Wei Li, and Wei Zhu
- Subjects
Cell Extracts ,Liver Cirrhosis ,Epithelial-Mesenchymal Transition ,Cellular differentiation ,Smad Proteins ,Biology ,Exosomes ,Collagen Type I ,Cell Line ,Umbilical Cord ,Transforming Growth Factor beta1 ,Mice ,Liver disease ,Original Research Reports ,medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Carbon Tetrachloride ,Cell Shape ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,medicine.disease ,Transplantation ,Collagen Type III ,Liver ,Cell culture ,Immunology ,Cancer research ,Liver function ,Signal Transduction ,Developmental Biology ,Transforming growth factor - Abstract
Mesenchymal stem cells (MSCs) have been considered as an attractive tool for the therapy of diseases. Exosomes excreted from MSCs can reduce myocardial ischemia/reperfusion damage and protect against acute tubular injury. However, whether MSC-derived exosomes can relieve liver fibrosis and its mechanism remain unknown. Previous work showed that human umbilical cord-MSCs (hucMSCs) transplanted into acutely injured and fibrotic livers could restore liver function and improve liver fibrosis. In this study, it was found that transplantation of exosomes derived from hucMSC (hucMSC-Ex) reduced the surface fibrous capsules and got their textures soft, alleviated hepatic inflammation and collagen deposition in carbon tetrachloride (CCl4)-induced fibrotic liver. hucMSC-Ex also significantly recovered serum aspartate aminotransferase (AST) activity, decreased collagen type I and III, transforming growth factor (TGF)-β1 and phosphorylation Smad2 expression in vivo. In further experiments, we found that epithelial-to-mesenchymal transition (EMT)-associated markers E-cadherin-positive cells increased and N-cadherin- and vimentin-positive cells decreased after hucMSC-Ex transplantation. Furthermore, the human liver cell line HL7702 underwent typical EMT after induction with recombinant human TGF-β1, and then hucMSC-Ex treatment reversed spindle-shaped and EMT-associated markers expression in vitro. Taken together, these results suggest that hucMSC-Ex could ameliorate CCl4-induced liver fibrosis by inhibiting EMT and protecting hepatocytes. This provides a novel approach for the treatment of fibrotic liver disease.
- Published
- 2013
36. 3,3'-Diindolylmethane stimulates exosomal Wnt11 autocrine signaling in human umbilical cord mesenchymal stem cells to enhance wound healing
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Fei Mao, Xiao Xu, Hui Shi, Zhaoji Pan, Aihua Gong, Bin Zhang, Yaoxiang Sun, Rong Li, Yongmin Yan, Wenrong Xu, Xu Zhang, Hui Qian, and Jiahao Xu
- Subjects
0301 basic medicine ,3,3'-Diindolylmethane ,exosome ,Indoles ,genetic structures ,Medicine (miscellaneous) ,Diindolylmethane ,Exosome ,Regenerative medicine ,Umbilical Cord ,03 medical and health sciences ,chemistry.chemical_compound ,Animals ,Humans ,Autocrine signalling ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cells, Cultured ,Wound Healing ,Chemistry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Rats ,Wnt Proteins ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,sense organs ,Stem cell ,Wound healing ,Burns ,3,3′-diindolylmethane ,Signal Transduction ,Research Paper ,Wnt11 - Abstract
Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are suggested as a promising therapeutic tool in regenerative medicine, however, their efficacy requires improvement. Small molecules and drugs come up to be a convenient strategy in regulating stem cells fate and function. Here, we evaluated 3,3'-diindolylmethane (DIM), a natural small-molecule compound involved in the repairing effects of hucMSCs on a deep second-degree burn injury rat model. HucMSCs primed with 50 μM of DIM exhibited desirable repairing effects compared with untreated hucMSCs. DIM enhanced the stemness of hucMSCs, which was related to the activation of Wnt/β-catenin signaling. β-catenin inhibition impaired the healing effects of DIM-primed hucMSCs (DIM-hucMSCs) in vivo. Moreover, we demonstrated that DIM upregulated Wnt11 expression in hucMSC-derived exosomes. Wnt11 knockdown inhibited β-catenin activation and stemness induction in DIM-hucMSCs and abrogated their therapeutic effects in vivo. Thus, our findings indicate that DIM promotes the stemness of hucMSCs through increased exosomal Wnt11 autocrine signaling, which provides a novel strategy for improving the therapeutic effects of hucMSCs on wound healing.
- Published
- 2016
37. Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy
- Author
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Cheng Ji, Jing Yu, Yongmin Yan, Lei Yin, Bingying Wang, Hui Qian, Juanjuan Wang, Haoyuan Jia, Wenrong Xu, Xueming Zhu, and Bin Zhang
- Subjects
0301 basic medicine ,Medicine (miscellaneous) ,Gene Expression ,Exosomes ,Autophagy-Related Protein 7 ,Autophagy-Related Protein 5 ,Umbilical Cord ,Rats, Sprague-Dawley ,0302 clinical medicine ,Renal capsule ,lcsh:QD415-436 ,Nephrotoxicity ,lcsh:R5-920 ,Nephritis ,Cell Differentiation ,medicine.anatomical_structure ,Human umbilical cord mesenchymal stem cell ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,lcsh:Medicine (General) ,Microtubule-Associated Proteins ,medicine.drug ,ATG5 ,Primary Cell Culture ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Exosome ,Cell Line ,lcsh:Biochemistry ,03 medical and health sciences ,Fetus ,medicine ,Autophagy ,Animals ,Humans ,Cisplatin ,Sirolimus ,Adenine ,Research ,Epithelial Cells ,Mesenchymal Stem Cells ,Cell Biology ,Fibroblasts ,Rats ,030104 developmental biology ,Immunology ,Cancer research ,Biomarkers - Abstract
Background The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo. Methods In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated. Results hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals. Conclusions Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of cisplatin. Therefore, pre-treatment of hucMSC-Ex may be a new method to improve the therapeutic effect of cisplatin. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0463-4) contains supplementary material, which is available to authorized users.
- Published
- 2016
38. Exosomes Derived from Akt-Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis via Activating Platelet-Derived Growth Factor D
- Author
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Jie Ma, Xiaosu Zhao, Wenrong Xu, Li Sun, Xiaoxian Sun, Hui Qian, Wei Zhu, Xiaochun Sun, and Yuanyuan Zhao
- Subjects
0301 basic medicine ,Angiogenesis ,medicine.medical_treatment ,Neovascularization, Physiologic ,Apoptosis ,Cardioprotection ,Biology ,Exosomes ,Cell Line ,Umbilical Cord ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Translational Research Articles and Reviews ,Cell Movement ,medicine ,Animals ,Humans ,Regeneration ,Receptors, Platelet-Derived Growth Factor ,Protein kinase B ,Cell Proliferation ,Platelet-Derived Growth Factor ,Lymphokines ,Wound Healing ,Growth factor ,Myocardium ,Akt ,Platelet‐derived growth factor D ,Mesenchymal stem cell ,Endothelial Cells ,Heart ,Mesenchymal Stem Cells ,Cell Biology ,General Medicine ,Microvesicles ,Endothelial stem cell ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,biology.protein ,Stem cell ,Chickens ,Proto-Oncogene Proteins c-akt ,Platelet-derived growth factor receptor ,Developmental Biology ,Tissue‐Specific Progenitor and Stem Cells - Abstract
We have previously demonstrated the cardioprotective effects of exosomes derived from mesenchymal stem cells (MSCs). It is well known that the activation of Akt is involved in stem cell-induced cardioprotection. In the present study, we investigated whether exosomes released from Akt-overexpressing MSCs showed a beneficial effect on cardioprotection and angiogenesis. MSCs were collected from human umbilical cord (hucMSCs), and Akt was transfected into hucMSCs (Akt-hucMSCs) by using an adenovirus transfection system. Exosomes were isolated from control hucMSCs (Exo) and Akt-hucMSCs (Akt-Exo). An acute myocardial infarction model was created by ligation of the left anterior decedent coronary artery (LAD) in rats. Various source exosomes (400 µg of protein) were infused via the tail vein immediately after LAD ligation. The cardiac function was evaluated by using echocardiography after different treatments for 1 and 5 weeks, respectively. Endothelial cell proliferation, migration, and tube-like structure formation, as well as chick allantoic membrane assay, were used to evaluate the angiogenetic effects of Akt-Exo. The results indicated that cardiac function was significantly improved in the animals treated with Akt-Exo. In addition, Akt-Exo significantly accelerated endothelial cell proliferation and migration, tube-like structure formation in vitro, and blood vessel formation in vivo. The expression of platelet-derived growth factor D (PDGF-D) was significantly upregulated in Akt-Exo. However, the angiogenesis was abrogated in endothelial cells treated with the exosomes obtained from MSCs transfected with PDGF-D-siRNA. Our studies suggest that exosomes obtained from Akt-modified hucMSCs are more effective in myocardial infarction therapy through promoting angiogenesis. PDGF-D plays an important role in Akt-Exo-mediated angiogenesis.
- Published
- 2016
39. Mesenchymal stem cell-secreted soluble signaling molecules potentiate tumor growth
- Author
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Fei Mao, Hui Qian, Yongmin Yan, Wei Zhu, Xiuhong Shan, Wenrong Xu, Ling Huang, Xiaosheng Wu, and Yahong Li
- Subjects
Vascular Endothelial Growth Factor A ,Cell signaling ,Epithelial-Mesenchymal Transition ,Cell Survival ,MAP Kinase Signaling System ,Angiogenesis ,Chick Embryo ,Biology ,Chorioallantoic Membrane ,Mice ,GTP-Binding Proteins ,Image Processing, Computer-Assisted ,Animals ,Humans ,Epithelial–mesenchymal transition ,Stem Cell Niche ,Molecular Biology ,Cell Proliferation ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,Cell growth ,Mesenchymal stem cell ,Intracellular Signaling Peptides and Proteins ,Mesenchymal Stem Cells ,Neoplasms, Experimental ,U937 Cells ,Cell Biology ,Magnetic Resonance Imaging ,Xenograft Model Antitumor Assays ,Coculture Techniques ,In vitro ,Cell biology ,Tumor progression ,Culture Media, Conditioned ,Apoptosis Regulatory Proteins ,rhoA GTP-Binding Protein ,Reprogramming ,Developmental Biology - Abstract
In previous studies, we and others have shown that bone marrow mesenchymal stem cells (MSCs) are recruited to sites of growing tumors and promote tumor growth in mouse xenograft models, suggesting that interactions between MSCs and tumor cells may play an important role in this process. However, the exact mechanism remains unclear. In the present study, we investigated whether the physical presence or the continuous presence of MSCs is required for enhanced tumor growth, and we found that pretreatment of tumor cells SGC-7901 with a single dose of human MSC-conditioned medium (hMSC-CM) in vitro is sufficient to potentiate tumor growth comparable to the effect of MSC co-injection in vivo in mouse xenograft models. We further showed that significant tumor modifying activity is present in post-ultracentrifigation soluble fraction. Biochemical analysis suggests that hMSC-CM induces the expression of VEGF of tumor cells as well as the activation of RhoA-GTPase and ERK1/2. Furthermore, hMSC-CM-enhanced tumor growth is sustainable in serial transplantation, suggesting that MSC-secreted factors have profound effects on "reprogramming" of tumor growth. Our data provide new insights into the way in which MSCs modify tumor growth and offer a new and exciting opportunity to develop effective therapeutics for intercepting tumor progression.
- Published
- 2011
40. Mesenchymal stem cells modified to express lentivirus TNF-α Tumstatin45-132 inhibit the growth of prostate cancer
- Author
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Wenrong Xu, Wei Zhu, Hui Qian, Xu Zhang, and Ruiwen Zhang
- Subjects
Male ,Tumstatin ,Recombinant Fusion Proteins ,Mice, Nude ,Apoptosis ,Biology ,Mice ,Prostate cancer ,Transduction, Genetic ,Cancer stem cell ,Cell Line, Tumor ,LNCaP ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Extracellular Signal-Regulated MAP Kinases ,Cell Proliferation ,mesenchymal stem cells ,Mice, Inbred BALB C ,Lentivirus ,Mesenchymal stem cell ,JNK Mitogen-Activated Protein Kinases ,NF-kappa B ,Prostatic Neoplasms ,Articles ,Genetic Therapy ,Cell Biology ,prostate cancer ,medicine.disease ,gene therapy ,Xenograft Model Antitumor Assays ,Molecular biology ,Coculture Techniques ,Rats ,TNF-α ,Cancer cell ,Cancer research ,Molecular Medicine ,Tumor necrosis factor alpha ,Proto-Oncogene Proteins c-akt - Abstract
Mesenchymal stem cells (MSCs) are a potential novel delivery system for cell-based gene therapies. Although tumour necrosis factor (TNF)-α has been shown to have antitumour activity, its use in therapy is limited by its systemic toxicity. For the present study, we designed lentivirus-mediated signal peptide TNF-α-Tumstatin(45-132) -expressing mesenchymal stem cells (SPTT-MSCs) as a novel anti-cancer approach. We evaluated the effects of this approach on human prostate cancer cells (PC3 and LNCaP) by co-culturing them with either SPTT-MSCs or supernatants from their culture medium in vitro. The antitumour effects and possible mechanisms of action of SPTT-MSCs were then determined in PC3 cells in vivo. The results showed that efficient TNF-α-Tumstatin(45-132) -expressing MSCs had been established, and demonstrated that SPTT-MSCs inhibited the proliferation of and induced apoptosis in prostate cancer cells and xenograft tumours. As would be expected, given the properties of the individual proteins, the TNF-α-Tumstatin(45-132) fusion exerted potent cytotoxic effects on human prostate cancer cells and tumours via the death receptor-dependent apoptotic pathway and via antiangiogenic effects. Our findings suggest that SPTT-MSCs have significant activity against prostate cancer cells, and that they may represent a promising new therapy for prostate cancer.
- Published
- 2011
41. Isolation of cancer stem cells from transformed human mesenchymal stem cell line F6
- Author
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Hui Qian, Wenrong Xu, Xuejing Xu, Yongmin Yan, Wei Zhu, Mei Wang, and Xu Zhang
- Subjects
Male ,Cellular differentiation ,Molecular Sequence Data ,Mice, Nude ,Cell Separation ,Biology ,Stem cell marker ,Mice ,Antigens, CD ,Cancer stem cell ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,AC133 Antigen ,neoplasms ,Genetics (clinical) ,Cell Line, Transformed ,Cell Proliferation ,Glycoproteins ,Mice, Inbred BALB C ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Flow Cytometry ,carbohydrates (lipids) ,Endothelial stem cell ,Cell culture ,embryonic structures ,Immunology ,Neoplastic Stem Cells ,Cancer research ,Molecular Medicine ,Stem cell ,Peptides ,Neoplasm Transplantation ,Signal Transduction ,Adult stem cell - Abstract
Cancer stem cells (CSCs) have the characteristics of self-renewal, unlimited proliferation, and initiating new tumors. However, the origin of CSCs is still controversial. F6, a tumor cell line transformed from human fetal mesenchymal stem cells, was established in our previous study. Whether CSCs exist in this mutated cell line remains unclear. In the present study, we isolated CSCs from F6 cells based on CD133 expression using flow cytometry and investigated the biological characteristics of CD133+ F6 cells (F6-CD133+). We observed that the F6-CD133+ cells grew faster and had a higher capacity of colony formation than the F6-CD133- cells and parental F6 cells in vitro. In addition, F6-CD133+ cells had a higher tumorigenic ability than F6-CD133- cells in vivo since 1,000 F6-CD133+ cells were able to form tumors in nude mice. Cell viability assay revealed that F6-CD133+ cells were more sensitive to cisplatin while less to 5-fluorouracil. Furthermore, gene expression profile analysis showed that there were 673 differentially expressed genes between F6-CD133+ and F6-CD133- cells, many of which were involved in key cell signaling pathways. Taken together, our findings confirm that F6 cells contain a population of CSCs that contribute to its heterogeneity and tumorigenic potential, indicating that transformed stem cells could be the source of CSCs, and targeting this population may lead to more effective tumor treatments.
- Published
- 2010
42. Safety evaluation of exosomes derived from human umbilical cord mesenchymal stromal cell
- Author
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Yuanyuan Zhao, Yuping Duan, Xiaoxian Sun, Rongman Xu, Li Sun, Hui Qian, Wenrong Xu, Yiwen Han, and Wei Zhu
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Stromal cell ,Immunology ,Guinea Pigs ,H&E stain ,Myocardial Infarction ,Exosomes ,Mesenchymal Stem Cell Transplantation ,Umbilical cord ,Hemolysis ,Umbilical Cord ,Rats, Sprague-Dawley ,03 medical and health sciences ,In vivo ,Internal medicine ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Genetics (clinical) ,Cells, Cultured ,Transplantation ,Hematology ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Microvesicles ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Liver ,Female ,Rabbits ,business - Abstract
Background aims Mounting evidence shows that non–cell-based transplantation of exosomes derived from mesenchymal stromal cells (MSCs) has more potential protective and reparative effects than MSCs have. However, whether it is safe to transplant MSC exosomes into tissues is still not clear. In this study, we evaluated the safety of transplantation of exosomes derived from human umbilical cord MSCs (hucMSC exosomes). Methods hucMSC exosomes were incubated with the cardiac blood from a healthy rabbit, and hemolysis was observed. For analysis of vascular and muscle stimulation, pyrogen, systemic anaphylaxis and hematology indexes, hucMSC exosomes were given to rabbits, guinea pigs and rats. The histological changes in the vascular and muscle sites of injection in rabbits were analyzed by hematoxylin and eosin staining. Allergy symptoms in guinea pigs and rectal temperature of rabbits were observed and recorded. To study safety in vivo , hucMSC exosomes were infused intravenously into rats with acute myocardial infarction. Rats' weight was measured and tail vein blood was collected to evaluate liver and renal function. Results hucMSC exosomes had a protective effect on weight loss and had no adverse effects on liver or renal function. Other detections, such as hemolysis, vascular and muscle stimulation, systemic anaphylaxis, pyrogen and hematology indexes, also showed that hucMSC exosomes were applicable. Conclusions hucMSC exosomes are well tolerated in animal models. This study provides evidence for the safety of intravenous infusion in future clinical therapy.
- Published
- 2015
43. Exosomes derived from human mesenchymal stem cells promote gastric cancer cell growth and migration via the activation of the Akt pathway
- Author
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Pengcheng Jiang, Xu Zhang, Wenrong Xu, Hongbing Gu, Hui Qian, Yongchang Chen, Mei Wang, Wei Zhu, and Runbi Ji
- Subjects
0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Cell ,Biology ,Exosomes ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,Genetics ,medicine ,Tumor Microenvironment ,Humans ,Epithelial–mesenchymal transition ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Cell Proliferation ,Tumor microenvironment ,Oncogene ,digestive, oral, and skin physiology ,Mesenchymal stem cell ,Stomach ,Mesenchymal Stem Cells ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Gastric Mucosa ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Molecular Medicine ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Mesenchymal stem cells (MSCs) are a component of the tumor microenvironment and can promote the development of gastric cancer through paracrine mechanism. However, the effects of MSC‑exosomes (MSC‑ex) on gastric cancer are less clear. The present study reported that MSC‑ex promoted the proliferative and metastatic potential of gastric cancer cells ex vivo. It was found that MSC‑ex enhanced the migration and invasion of HGC‑27 cells via the induction of the epithelial‑mesenchymal transition. MSC‑ex increased the expression of mesenchymal markers and reduced the expression of epithelial markers in gastric cancer cells. MSC‑ex also enhanced the tumorigenicity of gastric cancer cells ex vivo. MSC‑ex induced the stemness of gastric cancer cells. The expression of octamer‑binding transcription factor 4, ex determining region Y‑box 2 and Lin28B significantly increased in gastric cancer cells treated with MSC‑ex. The present study further demonstrated that MSC‑ex elicited these biological effects predominantly via the activation of the protein kinase B signaling pathway. Taken together, the present findings provided novel evidence for the role of MSC‑ex in gastric cancer and a new opportunity for improving the efficiency of gastric cancer treatment by targeting MSC‑ex.
- Published
- 2015
44. Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer
- Author
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Xiao Yuan, Bin Zhang, Wenrong Xu, Runbi Ji, Yongmin Yan, Xu Zhang, Hui Qian, Jianguo Xue, Mei Wang, and Wei Zhu
- Subjects
MAPK/ERK pathway ,Male ,Cell signaling ,Antimetabolites, Antineoplastic ,MAP Kinase Signaling System ,Mice, Nude ,Apoptosis ,Cell Communication ,Biology ,Mitogen-activated protein kinase kinase ,Exosomes ,Mice ,Stomach Neoplasms ,Cell Line, Tumor ,Report ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Extracellular Signal-Regulated MAP Kinases ,Molecular Biology ,Mitogen-Activated Protein Kinase Kinases ,Mice, Inbred BALB C ,Kinase ,Mesenchymal stem cell ,Cancer ,Membrane Transport Proteins ,Mesenchymal Stem Cells ,Cell Biology ,medicine.disease ,Microvesicles ,Cell biology ,Enzyme Activation ,Drug Resistance, Neoplasm ,Cancer cell ,RNA Interference ,raf Kinases ,Fluorouracil ,Guanylate Kinases ,Developmental Biology - Abstract
Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer.
- Published
- 2015
45. Deregulated microRNAs in gastric cancer tissue-derived mesenchymal stem cells: novel biomarkers and a mechanism for gastric cancer
- Author
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Jie Cai, Xiaojun Wu, Hui Qian, Feng Huang, Tingting Yang, Chonghui Zhao, Hui Shi, Q Zhu, Lubin Zhang, Mei Wang, Wenrong Xu, Shui Wang, Bin Zhang, Xu Zhang, and Wenshuai Zhu
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,Down-Regulation ,Mice, Nude ,Biology ,Exosomes ,Paracrine signalling ,Mice ,Downregulation and upregulation ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,microRNA ,Paracrine Communication ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Molecular Diagnostics ,Cell Proliferation ,Mice, Inbred BALB C ,mesenchymal stem cells ,gastric cancer ,Mesenchymal stem cell ,Cancer ,medicine.disease ,Microvesicles ,Up-Regulation ,MicroRNAs ,Oncology ,Lymphatic Metastasis ,Cancer cell ,Cancer research ,cross-talk ,tumour microenvironment - Abstract
Background: MicroRNAs (miRNAs) are involved in gastric cancer development and progression. However, the expression and role of miRNAs in gastric cancer stromal cells are still unclear. Methods: The miRNAs differentially expressed in gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) relative to adjacent non-cancerous tissue-derived MSCs (GCN-MSCs) and in cancer tissues relative to adjacent non-cancerous tissues were screened using miRNA microarray and validated by quantitative RT–PCR. The impact of GC-MSCs on HGC-27 cells was observed in vitro using colony formation and transwell assays, and these cells were subcutaneously co-injected into mice to assess tumour growth in vivo. Exogenous downregulation of miR-221 expression in cells was achieved using an miRNA inhibitor. Results: miR-214, miR-221 and miR-222 were found to be commonly upregulated in GC-MSCs and cancer tissues. Their levels were tightly associated with lymph node metastasis, venous invasion and the TNM stage. Gastric cancer tissue-derived mesenchymal stem cells significantly promoted HGC-27 growth and migration and increased the expression of miR-221 via paracrine secretion, and the targeted inhibition of miR-221 in GC-MSCs could block its tumour-supporting role. GC-MSC-derived exosomes were found to deliver miR-221 to HGC-27 cells and promoted their proliferation and migration. Conclusions: Gastric cancer tissue-derived mesenchymal stem cells favour gastric cancer progression by transferring exosomal miRNAs to gastric cancer cells, thus providing a novel mechanism for the role of GC-MSCs and new biomarkers for gastric cancer.
- Published
- 2013
46. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro
- Author
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Wei Zhu, Wenrong Xu, Huitao Xu, Hui Qian, Bingying Wang, Mei Wang, Bin Zhang, Yongmin Yan, Ying Zhou, Hongbing Gu, Huiyi Wu, Fei Mao, Yang Tao, and Shuo Gao
- Subjects
Cellular differentiation ,Proliferation ,Medicine (miscellaneous) ,Apoptosis ,Exosomes ,medicine.disease_cause ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Exosome ,Umbilical Cord ,Nephrotoxicity ,medicine ,Animals ,Humans ,Cisplatin ,Chemistry ,Research ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Acute kidney injury ,Cell biology ,Oxidative Stress ,Cancer research ,Molecular Medicine ,Female ,Stem cell ,Human umbilical cord mesenchymal stem cells ,Oxidative stress ,medicine.drug - Abstract
Introduction Administration of bone marrow mesenchymal stem cells (MSCs) or secreted microvesicles improves recovery from acute kidney injury (AKI). However, the potential roles and mechanisms are not well understood. In the current study, we focused on the protective effect of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) on cisplatin-induced nephrotoxicity in vivo and in vitro. Methods We constructed cisplatin-induced AKI rat models. At 24 h after treatment with cisplatin, hucMSC-ex were injected into the kidneys via the renal capsule; human lung fibroblast (HFL-1)-secreted exosomes (HFL-1-ex) were used as controls. All animals were killed at day 5 after administration of cisplatin. Renal function, histological changes, tubular apoptosis and proliferation, and degree of oxidative stress were evaluated. In vitro, rat renal tubular epithelial (NRK-52E) cells were treated with or without cisplatin and after 6 h treated with or without exosomes. Cells continued to be cultured for 24 h, and were then harvested for western blotting, apoptosis and detection of degree of oxidative stress. Results After administration of cisplatin, there was an increase in blood urea nitrogen (BUN) and creatinine (Cr) levels, apoptosis, necrosis of proximal kidney tubules and formation of abundant tubular protein casts and oxidative stress in rats. Cisplatin-induced AKI rats treated with hucMSC-ex, however, showed a significant reduction in all the above indexes. In vitro, treatment with cisplatin alone in NRK-52E cells resulted in an increase in the number of apoptotic cells, oxidative stress and activation of the p38 mitogen-activated protein kinase (p38MAPK) pathway followed by a rise in the expression of caspase 3, and a decrease in cell multiplication, while those results were reversed in the hucMSCs-ex-treated group. Furthermore, it was observed that hucMSC-ex promoted cell proliferation by activation of the extracellular-signal-regulated kinase (ERK)1/2 pathway. Conclusions The results in the present study indicate that hucMSC-ex can repair cisplatin-induced AKI in rats and NRK-52E cell injury by ameliorating oxidative stress and cell apoptosis, promoting cell proliferation in vivo and in vitro. This suggests that hucMSC-ex could be exploited as a potential therapeutic tool in cisplatin-induced nephrotoxicity.
- Published
- 2013
47. 5-Azacytidine Induces Cardiac Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells by Activating Extracellular Regulated Kinase
- Author
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Lingyun Sun, Wei Zhu, Shengqin Ye, Hui Qian, Xu Zhang, Qian Qian, Wei Li, Wenrong Xu, Xiujuan Peng, Yongmin Yan, and Zhe Xu
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MAPK/ERK pathway ,STAT3 Transcription Factor ,Enzyme Activators ,Gene Expression ,Muscle Proteins ,MADS Domain Proteins ,Biology ,Umbilical Cord ,Original Research Reports ,Gene expression ,Nitriles ,Butadienes ,Myocyte ,Humans ,Myocytes, Cardiac ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Cell Shape ,Protein kinase C ,Cells, Cultured ,Kinase ,MEF2 Transcription Factors ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,Molecular biology ,Antigens, Differentiation ,Cell biology ,stomatognathic diseases ,Myogenic Regulatory Factors ,Azacitidine ,Desmin ,Signal transduction ,Developmental Biology - Abstract
5-Azacytidine (5-Aza) induces differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes. However, the underlying mechanisms are not well understood. Our previous work showed that 5-Aza induces human bone marrow-derived MSCs to differentiate into cardiomyocytes. Here, we demonstrated that 5-Aza induced cardiac differentiation of human umbilical cord-derived MSCs (hucMSCs) and explored the potential signaling pathway. Our results showed that hucMSCs had cardiomyocyte phenotypes after 5-Aza treatment. In addition, myogenic cells differentiated from hucMSCs were positive for mRNA and protein of desmin, β-myosin heavy chain, cardiac troponin T, A-type natriuretic peptide, and Nkx2.5. Human diploid lung fibroblasts treated with 5-Aza expressed no cardiac-specific genes. 5-Aza did not induce hucMSCs to differentiate into osteoblasts. Further study revealed that 5-Aza treatment activated extracellular signal related kinases (ERK) in hucMSCs, but protein kinase C showed no response to 5-Aza administration. U0126, a specific inhibitor of ERK, could inhibit 5-Aza-induced expression of cardiac-specific genes and proteins in hucMSCs. Increased phosphorylation of signal transducers and activators of transcription 3, and up-regulation of myocyte enhancer-binding factor-2c and myogenic differentiation antigen in 5-Aza-treated hucMSCs were also suppressed by U0126. Taken together, these results suggested that sustained activation of ERK by 5-Aza contributed to the induction of the differentiation of hucMSCs into cardiomyocytes in vitro.
- Published
- 2011
48. Mesenchymal stem cells derived from human umbilical cord ameliorate ischemia/reperfusion-induced acute renal failure in rats
- Author
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Yuan Chen, Ying Xie, Mei Wang, Xu Zhang, Wei Zhu, Huiling Cao, Hui Qian, Yongming Yan, and Wenrong Xu
- Subjects
Serum ,Pathology ,medicine.medical_specialty ,Ischemia ,Cell- and Tissue-Based Therapy ,Bioengineering ,Inflammation ,Kidney ,Applied Microbiology and Biotechnology ,Umbilical cord ,Umbilical Cord ,Cell therapy ,Rats, Sprague-Dawley ,Proliferating Cell Nuclear Antigen ,medicine ,Animals ,Humans ,Urea ,business.industry ,Mesenchymal stem cell ,Transdifferentiation ,Mesenchymal Stem Cells ,General Medicine ,Acute Kidney Injury ,medicine.disease ,Rats ,medicine.anatomical_structure ,Creatinine ,Immunology ,Reperfusion ,Female ,medicine.symptom ,Stem cell ,business ,Biotechnology - Abstract
Mesenchymal stem cells (MSCs) are candidates for cell therapy of kidney diseases. However, the application of MSC derived from human umbilical cord (UC-MSC) in treating acute renal failure (ARF) has not been reported. UC-MSCs, 10(6), were transplantated via the left carotid artery into ARF rats which was established by clamping bilateral pedicles for 60 min and reperfusing. Serum creatinine and urea nitrogen decreased 4.8 times and 3.6 times as well as caspase-3 and IL-1beta decreased 5.8 times and 9 times compared to control groups, respectively. The percent of proliferative cell nuclear antigen (PCNA)-positive cells (53% +/- 7.5%) was higher than that in the control groups (17% +/- 4.5%). In addition, the transplanted UC-MSCs could reside in local injury sites, leading to the relief of hyperemia and inflammation, but no obvious transdifferentiation into renal-like cells. The results lay the foundation for further study on the potential application of UC-MSC in human disease.
- Published
- 2009
49. Histological type of oncogenity and expression of cell cycle genes in tumor cells from human mesenchymal stem cells
- Author
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Xingzhong Wang, Runqiu Jiang, Wei Zhu, Miao Chen, Chun Qiao, Wenrong Xu, Yongchang Chen, Hui Qian, and Huan Yang
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Cancer Research ,Telomerase ,Cellular differentiation ,Acid Phosphatase ,Cell Cycle Proteins ,Biology ,Cancer stem cell ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Biomarkers, Tumor ,Humans ,Telomerase reverse transcriptase ,Polycomb Repressive Complex 1 ,Tartrate-Resistant Acid Phosphatase ,Mesenchymal stem cell ,Nuclear Proteins ,Mesenchymal Stem Cells ,Oncogenes ,General Medicine ,Immunohistochemistry ,Genes, cdc ,Isoenzymes ,Repressor Proteins ,Endothelial stem cell ,Proto-Oncogene Proteins c-kit ,Oncology ,Cancer research ,Stem cell ,Adult stem cell - Abstract
In previous experiments, a novel tumor cell line, which was characterized by dominated F6 mutated from human mesenchymal stem cells (hMSCs), was developed. The mechanism and biological characteristics of this mutation are still unclear. In this study, the histological type of F6 cells was investigated by immunohistochemistry with specific markers: vimentin, CD117, desmin, NSE and vWF. The characteristics of proliferation and metastasis were shown by PCNA (proliferating cell nuclear antigen), and nm23 and cell cycle-related genes, such as p16, p21, p53 and pRb, were analyzed by RT-PCR and immunohistochemistry. The expression of hTRAP and BMI-1 were detected by real-time PCR and Western blotting. The activity of telomerase was analyzed by TRAP (telomerase repeat amplification protocol) assay. The results showed that multi-directional differentiation occurred in F6 cells, i.e., special markers of muscle, endothelial cell and nerve system were co-expressed in F6 cells, while hardly expressed in hMSCs. F6 cells maintained the same properties as of MSCs, such as negativity for both CD117 and vimentin. F6 cells exhibited strong positivity for PCNA and negativity for nm23. The cell cycle-related genes, such as p16, p21, p53 and pRb, were not detected in F6 cells, while the expression of hTRAP and BMI-1 was significantly higher. The activity of telomerase was also significantly higher in F6 cells than that in hMSCs. These findings indicated that multi-directional differentiation occurred during the transformation of hMSCs into F6 cells, and that the genes of cell cycle and cell senescence may also be associated with the neoplasia of adult stem cells.
- Published
- 2006
50. Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy.
- Author
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Bingying Wang, Haoyuan Jia, Bin Zhang, Juanjuan Wang, Cheng Ji, Xueming Zhu, Yongmin Yan, Lei Yin, Jing Yu, Hui Qian, and Wenrong Xu
- Subjects
EXOSOMES ,CISPLATIN ,NEPHROTOXICOLOGY ,MESENCHYMAL stem cells ,ENZYME-linked immunosorbent assay - Abstract
Background: The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo. Methods: In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated. Results: hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals. Conclusions: Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of cisplatin. Therefore, pre-treatment of hucMSC-Ex may be a new method to improve the therapeutic effect of cisplatin. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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