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Li T.,Jiangsu University | Yan Y.,Jiangsu University | Wang B.,Jiangsu University | Qian H.,Jiangsu University | And 8 more authors.
Stem Cells and Development | Year: 2013

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. © Copyright 2013, Mary Ann Liebert, Inc. 2013. Source


Zhang X.,Jiangsu University | Zhang L.,Jiangsu University | Xu W.,Jiangsu University | Qian H.,Jiangsu University | And 8 more authors.
Current Cancer Drug Targets | Year: 2013

The use of adult stem cells as gene delivery vehicles is a novel and attractive strategy for cancer therapy. Mesenchymal stem cells (MSCs) provide a promising source for stem cell-based gene therapies. Interleukin-24 (IL24) has been suggested as an effective anticancer agent. However, a lack of tumor-targeted delivery and a host immune response to viral vehicles has hindered its application for cancer therapy. In this study, we evaluated the effects of IL24 delivered by MSCs as a therapeutic approach for lung cancer. We engineered human umbilical cord-derived MSCs (UC-MSCs) to efficiently deliver secretable IL24. We observed that IL24-transduced UC-MSCs (IL24-MSCs) inhibited the growth of A549 lung cancer cells by induction of apoptosis and cell cycle arrest. The IL24 proteins secreted by IL24-MSCs were involved in regulating the ERK-1/2, AKT and JNK signaling pathways. Additionally, MSCs-mediated IL24 expression led to an increase in the cleavage of caspases-3/8/9 and PARP, the Bax/Bcl-2 ratio, as well as the p21 expression in A549 cells. We also demonstrated that injection of IL24-MSCs significantly suppressed xenograft tumor growth. Moreover, the IL24-MSCs had anti-angiogenic effects both in vitro and in vivo. Taken together, our findings indicate that IL24 delivered by human UC-MSCs has the potential to be used as an alternative strategy for lung cancer therapy. © 2013 Bentham Science Publishers. Source


Qian Q.,Jiangsu University | Qian H.,Jiangsu University | Zhang X.,Jiangsu University | Zhu W.,Jiangsu University | And 7 more authors.
Stem Cells and Development | Year: 2012

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. © 2012, Mary Ann Liebert, Inc. Source


Yang X.,Nantong University | Zhang M.,Nantong University | Zhang Y.,Nantong University | Li W.,Jiangsu Center for Stem Cell Engineering and Technology | Yang B.,Jiangsu Center for Stem Cell Engineering and Technology
Fertility and Sterility | Year: 2011

Objective: To investigate the effect of mesenchymal stem cells isolated from Wharton jelly of umbilical cord (WJ-MSCs) on ameliorating damaged human endometrial stromal cells (ESCs). Design: Experimental study. Setting: University-affiliated hospital. Patient(s): Sixteen endometrial tissues were obtained from women undergoing hysterectomy. Eight umbilical cords were obtained from full-term deliveries. Intervention(s): ESCs were cultured with mifepristone to get damaged ESCs, then damaged ESCs were co-cultured with WJ-MSCs. Main Outcome Measure(s): The proliferation of ESCs was investigated by Cell Counting Kit 8, and the percentage of apoptosis by annexin-V-fluorescein isothiocyanate binding. The mRNA and protein expression of vascular endothelial growth factor (VEGF) and caspases 3, 8, and 9 were determined by one-step quantitative real-time polymerase chain reaction and Western blot. Result(s): After exposure to mifepristone, the proliferation of ESCs decreased and the apoptosis percentage increased in a dose- and time-dependent manner. At a certain dose and duration, this damage continued even after the withdrawl of mifepristone at 48 hours. When the damaged ESCs were cocultured with WJ-MSCs, the proliferation of these damaged cells was significantly increased and apoptosis percentage decreased. In addition, the level of VEGF mRNA and protein decreased and that of caspases 3, 8, and 9 increased. Conclusion(s): WJ-MSCs may serve as a promising treatment approach to ameliorate endometrial damage. © 2011 American Society for Reproductive Medicine, Published by Elsevier Inc. Source


Chen Y.,Jiangsu University | Qian H.,Jiangsu University | Zhu W.,Jiangsu University | Zhang X.,Jiangsu University | And 5 more authors.
Stem Cells and Development | Year: 2011

Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are particularly attractive cells for cellular and gene therapy in acute kidney injury (AKI). Adenovirus-mediated gene therapy has been limited by immune reaction and target genes selection. However, in the present study, we investigated the therapeutic effects of hepatocyte growth factor modified hucMSCs (HGF-hucMSCs) in ischemia/reperfusion-induced AKI rat models. In vivo animal models were generated by subjecting to 60 min of bilateral renal injury by clamping the renal pedicles and then introduced HGF-hucMSCs via the left carotid artery. Our results revealed that serum creatinine and urea nitrogen levels decreased to the baseline more quickly in HGF-hucMSCs-treated group than that in hucMSCs- or green fluorescent protein-hucMSCs-treated groups at 72 h after injury. The percent of proliferating cell nuclear antigen-positive cells in HGF-hucMSCs-treated group was higher than that in the hucMSCs or green fluorescent protein-hucMSCs-treated groups. Moreover, injured renal tissues treated with HGF-hucMSCs also exhibited less hyperemia and renal tubule cast during the recovery process. Immunohistochemistry and living body imaging confirmed that HGF-hucMSCs localize to areas of renal injury. Real-time polymerase chain reaction result showed that HGF-hucMSCs also inhibited caspase-3 and interleukin-1β mRNA expression in injured renal tissues. Western blot also showed HGF-hucMSCs-treated groups had lower expression of interleukin-1β. Terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate (dUTP) nick end labeling method indicated that HGF-hucMSCs-treated group had the least apoptosis cells. In conclusion, our findings suggest that HGF modification promotes the amelioration of ischemia/reperfusion-induced rat renal injury via antiapoptotic and antiinflammatory mechanisms; thus, providing a novel therapeutic application for hucMSCs in AKI. © 2011 Mary Ann Liebert, Inc. Source

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