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Hong J.,Union Stem Cell and Gene Engineering Co. | Jin H.,Shanghai University | Han J.,Union Stem Cell and Gene Engineering Co. | Han J.,Peking Union Medical College | And 8 more authors.
Molecular Medicine Reports | Year: 2014

Cirrhosis is the long-term outcome of chronic hepatic injury and no effective therapy is currently available for this disease. Mesenchymal stromal cells (MSCs) are multi-potent cells that are easily acquired and amplified, and may be potential candidates for cell therapy against cirrhosis. This study aimed to determine the therapeutic effects of human umbilical cord-derived MSCs (hUCMSCs) for the treat ment of liver cirrhosis and identify an effective method for engrafting MSCs. The model of liver cirrhosis was established by induction of diethylnitrosamine (DEN) in rats. The isolated hUCMSCs were identified by morphology, flow cytometry and multilineage differentiation; they were injected into the vein of DEN-induced rats at varied cell doses and infusion times. Biochemical analyses of the serum and histopathological analysis of the liver tissues were performed to evaluate the therapeutic effects of hUCMSCs in all treatment groups. The results indicated that isolated hUCMSCs were capable of self-replication and differentiated into multiple lineages, including osteoblast-, adipocyte- and hepatocyte-like cells. Compared with the control group, administration of hUCMSCs at different cell doses and infusion times relieved DEN-induced cirrhosis to varying degrees. The therapeutic effects of hUCMSCs on liver cirrhosis gradually improved with increased cell dose and infusion times. The improvement of cirrhosis was due to the capacity of hUCMSCs to breakdown collagen fibers in the liver. It was demonstrated that infusion of hUCMSCs effectively relieved liver cirrhosis by facilitating the breakdown of collagen fibers in a dose-dependent manner and multiple infusions caused a relatively greater improvement in cirrhosis compared with a single infusion of hUCMSCs.


Zhang Y.-S.,Tianjin Central Hospital of Obstetrics and Gynecology | Lu Z.-Y.,Tianjin Central Hospital of Obstetrics and Gynecology | Lu Z.-Y.,Union Stem Cell and Gene Engineering Co. | Yu Y.,Peking University | And 4 more authors.
Journal of Assisted Reproduction and Genetics | Year: 2012

Purpose: Retinal pigment epithelium cells derived from human embryonic stem cells (ESCs) could be useful for restoring retinal function in age-related macular degeneration. However the use of non-human feeder cells to support the growth of ESCs for clinical applications raises the concern of possible contamination because of direct contact between animal and human cells. Methods: In this study, we produced human ESCs using human fibroblast feeder layers isolated from foreskin and abdominal tissues. Using this system, human ESCs differentiated into retinal pigment epithelium cells in differentiation medium. Results: Seven human ESC lines were established from 18 blastocysts. These human ESCs showed normal morphology, expressed all expected cell surface markers, had the ability to form embryoid bodies upon culture in vitro and teratomas after injection into SCID mice, and differentiated further into derivatives of all three germ layers. Under conditions of committed differentiation, these human ESCs could differentiate into retinal pigment epithelium cells after 2 months in culture. Conclusions: The results of this study demonstrated that human foreskin/abdominal fibroblasts have the potential to support the derivation and long-term culture of human ESCs, which can then be used to generate retinal pigment epithelium cells with characteristic morphology and molecular markers. This technique avoids the concerns of contamination from animal feeder layers during human ESC derivation, culture and differentiation, and will thus facilitate the development of retinal pigment epithelium cell transplantation therapy. © Springer Science+Business Media, LLC 2012.


Li W.-B.,Tianjin Medical University | Zhang Y.-S.,Union Stem Cell and Gene Engineering Co. | Lu Z.-Y.,Tianjin Central Hospital for Obstetrics and Gynecology | Lu Z.-Y.,Union Stem Cell and Gene Engineering Co. | And 4 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

PURPOSE. We investigated the potential of human parthenogenetic embryonic stem cells (hPESCs) to differentiate into RPE cells, and identified development-regulating microRNAs (miRNAs). METHODS. RPE cells were derived from hPESCs. The expression of markers and miRNA expression profiles during differentiation were studied by immunocytochemistry, real-time RT-PCR, and miRNA expression array at three time points. Human fetal RPE (hfRPE) cells also were analyzed. The target genes of candidate miRNAs then were validated. RESULTS. hPESC-derived RPE cells exhibited similar morphology and pigmentation to hfRPE cells. The expression of markers during differentiation indicated that the hPESC-derived RPE cells were immature. Most specific miRNAs had a role at some time point during the differentiation and maturation of RPE from hPESCs, except for two miRNAs (miR-204 and the miR- 302 family). The miR-204 was upregulated and miR-302 was down-regulated throughout the process. Subsequently, pigmented clusters and RPE signature gene expression increased significantly in the miR-204 overexpression group and miR-302 inhibition group compared to the control groups. CTNNBIP1 and TGFBR2 were confirmed to be the target genes of miR-204 and miR-302, respectively. CONCLUSIONS. hPESCs can develop into RPE-like cells and, thus, can be additional promising sources of RPE cells in cell therapy. The miR-204, miR-302s, and their targets are involved in regulating directed differentiation during the full course, thereby contributing to the search for a new method of improving differentiation efficiency using miRNAs. © 2012 The Association for Research in Vision and Ophthalmology, Inc.


Lu Z.-Y.,Tianjin Central Hospital of Obstetrics and Gynecology | Lu Z.-Y.,Union Stem Cell and Gene Engineering Co. | Dong R.,Tianjin Medical University | Li D.,Tianjin Medical University | And 4 more authors.
Oncology Reports | Year: 2012

Ovarian cancer is the fifth most common cancer among women worldwide. Detection of metastasis of ovarian cancer is crucial for diagnosis and prolongs the life of patients. This study focused on whether SNAI1 overexpression relates to invasion of ovarian cancer in vitro and in vivo. Invasion, colony formation and wound healing assays and flow cytometric analysis were performed to test the invasion and proliferation of SKOV3 ovarian cancer cells after transfection. The effect of SNAI1 on ovarian cancer in vivo was validated using a murine xenograft model. In vitro, SNAI1 upregulation led to an increased percent of CD133 + SKOV3 cells and promoted SKOV3 cell invasion and proliferation. In vivo, the SNAI1 overexpression group showed the highest rate of tumor growth compared with SNAI2 and the control group (60 and 50%, respectively). Our results show that SNAI1 expression induces an increase in the number of CD133 + cells, a change important for the epithelial to mesenchymal transition and the proliferation in ovarian cancer. It is suggested that SNAI1 may serve as a novel target for ovarian cancer prediction and therapy.


Li D.,Tianjin Medical University | Lu Z.,Union Stem Cell and Gene Engineering Co. | Lu Z.,Tianjin Central Hospital of Obstetrics and Gynecology | Jia J.,Tianjin Medical University | And 2 more authors.
JRAAS - Journal of the Renin-Angiotensin-Aldosterone System | Year: 2013

Introduction: Podocytes can respond to various injuries, including mechanical stress secondary to diabetic nephropathy (DN), which may cause deleterious adhesive effects on podocytes. Integrin α3β1 is the major podocyte adhesion molecule. In this study, we aim to investigate α3β1 expression and identify differentially expressed microRNAs in podocytes under mechanical stress compared with normal cells and podocytes under mechanical stress treated with spironolactone, respectively. Materials and methods: Serum and glucocorticoid induced kinase 1 (SGK1), mineralocorticoid receptor (MR) and integrin α3β1 were detected by Western blotting. The miRNA analyses were performed by TaqMan MicroRNA Array v2.0. Genes Itga3 and Itgb1 were analyzed for miRNA binding sites within 3'UTRs using TargetScan and PicTar. Results: Protein SGK1 and MR expression were significantly increased under mechanical stress and decreased after spironolactone treatment. Podocyte α3 and β1 expression were significantly decreased under mechanical stress and increased after spironolactone treatment. MiR-124, miR-190, miR-217 and miR-188 were the overlapped miRNAs that were upregulated under mechanical stress and downregulated after spironolactone treatment. MiR-124 was found to be a predicted miRNA target site in both Itga3 and Itgb1 3'UTRs. Conclusion: These results provide a novel idea that miR-124 might play an important role in podocytic adhesion damage under mechanical stress. © The Author(s) 2012.


Zou D.,Chinese Academy of Sciences | An G.,Chinese Academy of Sciences | Zhu G.,Chinese Academy of Sciences | Wang J.,Chinese Academy of Sciences | And 7 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Secondary monoclonal gammopathy of undetermined significance (MGUS) is a special phenomenon that occurs during the treatment of multiple myeloma (MM). The incidence, biological characteristics, and prognostic value of secondary MGUS in patients with MM remain undefined. We proceed with a retrospective systematic review of serum immunofixation electrophoresis studies performed in 438 cases of patients with plasma cell dyscrasias, including 409 cases of newly diagnosed MM and 29 cases of primary plasma cell leukemia. Secondary MGUS was more common in patients with myeloma who had undergone stem cell transplantation than in those who had not (17 [29.8%] of 57 versus 5 [1.4%] of 352, P<.001). The clinical parameters and cytogenetic characteristics in patients with or without secondary MGUS were comparable. The complete response rates in patients with or without secondary MGUS were 81.8% and 21.8% respectively (P<.01). For the cohort as a whole, secondary MGUS was associated with significantly prolonged progression-free survival (median, 52.0months versus 22.5months; P= .002) and overall survival (median, not reached versus 35.0months; P<.001). The presence of secondary MGUS retained independent prognostic value with a moderate impact on overall survival (hazard ratio .128 [95% confidence interval .018 to .922]; P= .041) in the multivariate Cox regression model. However, when analysis was restricted to patients undergoing stem cell transplantation, no statistical differences in progression-free survival and overall survival were found. In conclusion, we observe that secondary MGUS was frequently observed in MM patients after transplantation and conferred a survival prolongation. The favorable survival in patients with secondary MGUS may be explained by beneficial effect from myeloablative therapy. © 2014 American Society for Blood and Marrow Transplantation.


Liu Z.,Max Planck Institute for Heart and Lung Research | Liu Z.,Union Gene Test and Health Management Center | Yue S.,Max Planck Institute for Heart and Lung Research | Chen X.,Max Planck Institute for Heart and Lung Research | And 3 more authors.
Circulation Research | Year: 2010

RATIONALE: Polyploidy and multinucleation are characteristic features of mammalian cardiomyocytes, which develop shortly after birth when most differentiated cardiomyocytes become acytokinetic. Cardiac overload and hypertrophy further increase the degree of polyploidy of cardiomyocytes, suggesting a role in cell type-specific responses to physiological and pathological stimuli. OBJECTIVE: We sought to study the function of cyclinG1 in the regulation of polyploidy and multinucleation in cardiomyocytes. METHODS AND RESULTS: We found that expression of cyclinG1, a transcriptional target of p53, coincides with arrest of cardiomyocyte proliferation and onset of polyploidization. Overexpression of cyclinG1 promoted DNA synthesis but inhibited cytokinesis in neonatal cardiomyocytes leading to an enlarged population of binuclear cardiomyocytes. Reciprocally, inactivation of the cyclinG1 gene in mice lowered the degree of polyploidy and multinucleation in cardiomyocytes. Moreover, lack of cyclinG1 prevented the increase of polynucleated cardiomyocytes in response to pressure overload and hypertrophy. CONCLUSIONS: CyclinG1 is an important player for the regulation of polyploidy and multinucleation in cardiomyocytes probably by inhibition of apoptosis caused by checkpoint activation. © 2010 American Heart Association, Inc.


Geng Q.,Tianjin University of Traditional Chinese Medicine | Ni L.,Tianjin University of Traditional Chinese Medicine | Ouyang B.,Tianjin University of Traditional Chinese Medicine | Hu Y.,Union Stem Cell and Gene Engineering Co | And 2 more authors.
Reproductive Sciences | Year: 2016

Testis-specific genes are essential for the spermatogenesis in mammalian male reproduction. In this study, we have identified a novel testis-specific gene, Ccdc136 (coiled-coil domain containing 136), from the results of high-throughput gene expression profiling in the developmental stage of mouse testes. Ccdc136 was conserved across species in evolution. Quantitative real-time polymerase chain reaction and Western blot analyses showed that Ccdc136 messenger RNA and protein were extraordinarily expressed in mouse testes, which was first presented at postnatal 3 week and increased in an age-dependent manner before adulthood. Immunofluorescence staining revealed that CCDC136 protein was most abundantly located in the acrosome of round spermatids and elongating spermatids within seminiferous tubules of the adult mouse testes. To investigate the function of Ccdc136 in mouse testes, we generated the Ccdc136-knockout mice using Cas9/RNA-mediated gene targeting technology. Interestingly, we found Ccdc136-/- males were infertile, due to severe defect of disrupting acrosome formation. The expression levels of proteins (SPACA1 and PICK1) involved in acrosome formation were significantly downregulated in the testes of Ccdc136-/- mice than wide-type mice. Moreover, in vitro fertilization assay revealed that anti-CCDC136 antibody could remarkably inhibit fertilization, suggesting CCDC136 also plays an important role in fertilization. All of these demonstrated the essential role of CCDC136-mediated acrosome formation in spermatogenesis and fertilization, which might also provide new insight into the genetic causes of human infertility. © Society for Gynecologic Investigation.


Li D.,Tianjin Medical University | Lu Z.,Union Stem Cell and Gene Engineering Co. | Lu Z.,Tianjin University of Traditional Chinese Medicine | Jia J.,Tianjin Medical University | And 2 more authors.
Kidney and Blood Pressure Research | Year: 2014

Background/Aims: Curcumin, a kind of plant polyphenolic compound, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). Podocyte can respond to various injuries including mechanical stress secondary to DN. Our previous study showed that podocyte miR-124 expression was up-regulated accompanied with podocytic adhesive capacity damage in vitro and in vivo. We hypothesized, in the present research that curcumin would ameliorate podocyte adhesion damage under mechanical stress by inhibiting miR-124 expression. Methods: Gene expression of miR-124 was measured by real-time PCR and protein expression of integrin 3 was measured by Western blotting in STZ-induced uninephrectomized diabetic rats and cultured podocytes under mechanical stress treated with curcumin respectively. Western blot and luciferase reporter assays were used to detect the effects of miR-124 overexpression on the Itga3 expression in podocytes. Results: Gene expression of miR-124 was upregulated and 3 was downregulated in renal cortex of diabetic rats and cultured podocytes under mechanical stress which were ameliorated by curcumin treatment significantly. Transient co-transfection of miR-124 mimics with luciferase expression plasmids resulted in a significant repression of luciferase activity in podocytes. Mechanistically, Itga3 may be a regulation target of miR-124. Conclusions: These results provide a novel idea that curcumin prevents against podocytic adhesive capacity damage under mechanical stress by inhibitting miR-124 © 2014 S. Karger AG, Basel.


Ke B.,Tianjin Medical University | Song X.-N.,Union Stemcell and Gene Engineering Co. | Liu N.,Tianjin Medical University | Zhang R.-P.,Tianjin Medical University | And 2 more authors.
PLoS ONE | Year: 2014

Objective: The aim of this study was to investigate the prognostic value of metastatic lymph node ratio (LNR) in patients having radical resection for stage III gastric cancer. Methods: A total of 365 patients with stage III gastric cancer who underwent radical resection between 2002 and 2008 at Tianjin Medical University Cancer Institute and Hospital were analyzed. The cut-point survival analysis was adopted to determine the appropriate cutoffs for LNR. Kaplan-Meier survival curves and log-rank tests were used for the survival analysis. Results: By cut-point survival analysis, the LNR staging system was generated using 0.25 and 0.50 as the cutoff values. Pearson's correlation test revealed that the LNR was related with metastatic lymph nodes but not related with total harvested lymph nodes. Cox regression analysis showed that depth of invasion and LNR were the independent predictors of survival (p<0.05). There was a significant difference in survival between each pN stages classified by the LNR staging, however no significant difference was found in survival rate between each LNR stages classified by the pN staging. Conclusions: The LNR is an independent prognostic factor for survival in stage III gastric cancer and is superior to the pN category in TNM staging. It may be considered as a prognostic variable in future staging system. © 2014 Ke et al.

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