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Li T.,Shenzhen Beike Cell Engineering Research Institute | Li T.,Jilin University | Li T.,Stanford University | Chen H.,Central South University | And 8 more authors.
Human Molecular Genetics | Year: 2014

Aberrant imprinting of the insulin-like growth factor II (IGF2) gene is a molecular hallmark of many tumors. Reactivation of thenormally suppressed maternal allele leads to upregulation of the growth factor that promotes tumor growth. However, the mechanisms underlying the loss of imprinting (LOI) remain poorly defined. We examined the epigenotypes at the gene promoters that control IGF2 allelic expression. Using chromatin immunoprecipitation,wefound that in cells characterized by maintenance of IGF2 imprinting, three IGF2promoters were differentiallymodified, with the suppressed allele heavily methylated at histone H3K27 while the active allelewasunmethylated. In the LOI tumors,however, both alleleswere unmethylated,andcorrespondingly there wasnobinding of SUZ12, the docking factor of thepolycomb repressive complex 2 (PRC2),andof the zinc fingercontaining transcription factor (CTCF) that recruits the PRC2. Using chromatin conformation capture, we found that the CTCF-orchestrated intrachromosomal loop between the IGF2 promoters and the imprinting control region was abrogated in cells with LOI. SUZ12, which docks the PRC2 to IGF2 promoters for H3K27 methylation, was downregulated in LOI cells. These data reveal a new epigenetic control pathway related to the loss of IGF2 imprinting in tumors. © The Author 2013. Published by Oxford University Press. All rights reserved. Source


Liu M.,Guangzhou University | Wang J.,Guangzhou University | Hu X.,Shenzhen Beike Cell Engineering Research Institute | Xu J.,Email xufeili@vip.163.com
Zhonghua yi xue za zhi | Year: 2015

OBJECTIVE: To investigate the immumodulation ability of exosomes secreted from human umbilical cord-derived mesenchymal stem cells (hUC-MSCs).METHODS: hUC-MSCs were isolated and cultured.Exosomes were isolated from the culture media of the third-generation hUC-MSCs. The expression of specific surface marker CD9 and CD81 were detected by Western blot, and the concentration of hUC-MSCs exosomes(hUC-MSCs-ex) was evaluated by BCA assay. CD3/CD28-stimulated peripheral blood mononuclear cells(PBMCs) from healthy donor were co-cultured with different concentration of hUC-MSCs-ex for 72 h. The percentage of Th17 and Treg cells and the proliferation of CD4⁺ and CD8⁺ T cells were detected by flow cytometry. ELISA was used to test the level of IFN-γ, IL-6, TNF-α and TGF-β1.RESULTS: hUC-MSCs-ex inhibited the proliferation of CD4⁺ and CD8⁺ cells obviously,and increased the proportion of CD4⁺ CD25⁺ FoxP3⁺ Treg cells, with high expression of CD81 and CD9. After CD3/CD28 monoclonal antibody stimulated, the percentage of CD45⁺ CD4⁺ Ki67⁺ and CD45⁺ CD8⁺ Ki67⁺ cells were 85.3% ± 5.6% and 72.6% ± 6.3%, respectively. Meanwhile, the level of TGF-β1 were elevated and the level of IFN-γ, IL-6 and TNF-α were decreased (P<0.05).CONCLUSION: hUC-MSCs-ex has the immunomodulatory functionin vitro, which could be a new therapeutic agent for the treatment of immune disorders. Source


Liu M.,Guangzhou University | Wang J.,Guangzhou University | Hu X.,Guangzhou University | Hu X.,Shenzhen Beike Cell Engineering Research Institute | Xu J.,Guangzhou University
National Medical Journal of China | Year: 2015

Objective: To investigate the immumodulation ability of exosomes secreted from human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). Methods: hUC-MSCs were isolated and cultured. Exosomes were isolated from the culture media of the third-generation hUC-MSCs. The expression of specific surface marker CD9 and CD81 were detected by Western blot, and the concentration of hUC-MSCs exosomes(hUC-MSCs-ex) was evaluated by BCA assay. CD3/CD28-stimulated peripheral blood mononuclear cells(PBMCs) from healthy donor were co-cultured with different concentration of hUC-MSCs-ex for 72 h. The percentage of Thl7 and Treg cells and the proliferation of CD4+ and CD8+ T cells were detected by flow cytometry. ELISA was used to test the level of IFN-γ, IL-6, TNF-α and TGF-β1. Results: hUC-MSCs-ex inhibited the proliferation of CD4 and CD8+ cells obviously, and increased the proportion of CD4+ CD25+ FoxP3+ Treg cells, with high expression of CD81 and CD9. After CD3/CD28 monoclonal antibody stimulated, the percentage of CD45+ CD4+ Ki67+ and CD45+ CD8+ Ki67+ cells were 85.3% ±5.6% and 72.6% ± 6.3% Respectively. Meanwhile, the level of TGF-β1 were elevated and the level of IFN-γ, IL-6 and TNF-α were decreased (P <0.05). Conclusion: hUC-MSCs-ex has the immunomodulatory functionin vitro, which could be a new therapeutic agent for the treatment of immune disorders. Source


Feng M.,Guangdong Provincial Hospital of Chinese Medicine | Lu A.,Guangdong Provincial Hospital of Chinese Medicine | Gao H.,Guangdong Provincial Hospital of Chinese Medicine | Qian C.,Guangdong Provincial Hospital of Chinese Medicine | And 4 more authors.
Stem Cells International | Year: 2015

This retrospective study aimed to assess the safety of patients with severe cerebral palsy (CP), who received allogeneic umbilical cord blood stem cells (UCBSCs) treatment from August 2009 to December 2012 in Guangdong Provincial Hospital of Chinese Medicine. A total of 47 patients with average age of 5.85±6.12 years were evaluated in this study. There was no significant association with allogeneic UCBSCs treatments found in the data of the laboratory index. No casualties occurred. Some adverse events during treatments were found in 26 (55.3%) patients, including fever (42.6%) and vomiting (21.2%). Intrathecal infusion and the ages at the initiation of treatment (≤10 years old) were risk factors for the occurrence of adverse events by logistic regression analysis. However, all adverse events disappeared after symptomatic treatment. No treatment related serious adverse events were found in follow-up visits within 6 months. In conclusion, allogeneic UCBSCs treatment was relatively safe for severe CP patients. Copyright © 2015 Mei Feng et al. Source


Yang X.L.,The First Peoples Hospital of Foshan | Liu H.L.,General Hospital of Armed Police Forces | Yan X.Y.,Peking University | Wang Y.,Chinese PLA General Hospital | And 18 more authors.
BMC Medicine | Year: 2015

Background: The use of adult stem cells is limited by the quality and quantity of host stem cells. It has been demonstrated that Wharton's jelly-derived mesenchymal stem cells (WJMSCs), a primitive stromal population, could integrate into ischemic cardiac tissues and significantly improve heart function. In this randomized, controlled trial, our aim was to assess the safety and efficacy of intracoronary WJMSCs in patients with ST-elevation acute myocardial infarction (AMI). Methods: In a multicenter trial, 116 patients with acute ST-elevation MI were randomly assigned to receive an intracoronary infusion of WJMSCs or placebo into the infarct artery at five to seven days after successful reperfusion therapy. The primary endpoint of safety: the incidence of adverse events (AEs) within 18 months, was monitored and quantified. The endpoint of efficacy: the absolute changes in myocardial viability and perfusion of the infarcted region from baseline to four months, global left ventricular ejection fraction (LVEF) from baseline to 18 months were measured using F-18-fluorodeoxyglucose positron emission computed tomography (F-18-FDG-PET) and 99mTc-sestamibi single-photon emission computed tomography (99mTc-SPECT), and two-dimensional echocardiography, respectively. Results: During 18 months follow-up, AEs rates and laboratory tests including tumor, immune, and hematologic indexes were not different between the two groups. The absolute increase in the myocardial viability (PET) and perfusion within the infarcted territory (SPECT) was significantly greater in the WJMSC group [6.9 ± 0.6 % (95 %CI, 5.7 to 8.2)] and [7.1 ± 0.8 % (95 %CI, 5.4 to 8.8) than in the placebo group [3.3 ± 0.7 % (95 %CI, 1.8 to 4.7), P <0.0001] and 3.9 ± 0.6(95 %CI, 2.8 to 5.0), P = 0.002] at four months. The absolute increase in the LVEF at 18 months in the WJMSC group was significantly greater than that in the placebo group [7.8 ± 0.9 (6.0 to approximately 9.7) vs. 2.8 ± 1.2 (0.4 to approximately 5.1), P = 0.001]. Concomitantly, the absolute decreases in LV end-systolic volumes and end-diastolic volumes at 18 months in the WJMSC group were significantly greater than those in the placebo group (P = 0.0004, P = 0.004, respectively). Conclusions: Intracoronary infusion of WJMSCs is safe and effective in patients with AMI, providing clinically relevant therapy within a favorable time window. This study encourages additional clinical trials to determine whether WJMSCs may serve as a novel alternative to BMSCs for cardiac stem cell-based therapy. © 2015 Gao et al. Source

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