Xi Wang

Rutgers, The State University of New Jersey, Нью-Брансуик, New Jersey, United States

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Publications (50)129.21 Total impact

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    ABSTRACT: The purpose of this study was to propose a protocol for safe bicortical placement of mini-implants by measuring the interradicular spaces of the maxillary teeth and the bone quality. Cone-beam computed tomography data were obtained from 50 adults. Three-dimensional reconstructions and measurements were made with SimplantPro software (Materialise, Leuven, Belgium). For each interradicular site, the bone thicknesses and interradicular distances at the planes 1.5, 3, 6, and 9 mm above the cementoenamel junction were measured. Standard bone units were defined to evaluate the influences of bone density and the different placement patterns on the stability of the mini-implants. The safe interradicular sites in the maxilla for bicortical placement of 1.5-mm-diameter mini-implants were in all planes between the first and second premolars, and between the second premolar and the first molar. The safe palatal sites were between the first and second molars, and the safe labial sites of the 9-mm plane were between the central incisors, and between the lateral incisor and the canine. The safe buccal sites of the 6- and 9-mm planes were between the first and second molars, and the safe buccal sites of the 3-, 6-, and 9-mm planes were between the canine and the first premolar. Most bone thicknesses were from 8 to 12 mm. The optimal placement angle between the second premolar and the first molar was 58°. Bicortical placement could have more standard bone units than unicortical placement in the maxilla. Bicortical placement would be more stable in the maxilla. For the site between the molars, special care should be taken at a plane higher than 6 mm to prevent maxillary sinus penetration. The most favorable interradicular area in the maxilla was between the second premolar and the first molar. Copyright © 2015 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.
    American journal of orthodontics and dentofacial orthopedics: official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics 06/2015; 147(6). DOI:10.1016/j.ajodo.2015.02.018 · 1.38 Impact Factor
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    ABSTRACT: Macrophage activation and persistent inflammation contribute to the pathological process of spinal cord injury (SCI). It was reported that M2 macrophages were induced at 3-7 days after SCI but M2 markers were reduced or eliminated after 1 week. By contrast, M1 macrophage response is rapidly induced and then maintained at injured spinal cord. However, factors that modulate macrophage phenotype and function are poorly understood. We developed a model to distinguish bone-marrow derived macrophages (BMDMs) from residential microglia and explored how BMDMs change their phenotype and functions in response to the lesion-related factors in injured spinal cord. Infiltrating BMDMs expressing higher Mac-2 and lower CX3CR1 migrate to the epicenter of injury, while microglia expressing lower Mac-2 but higher CX3CR1 distribute to the edges of lesion. Myelin debris at the lesion site switches BMDMs from M2 phenotype towards M1-like phenotype. Myelin debris activates ATP-binding cassette transporter A1 (ABCA1) for cholesterol efflux in response to myelin debris loading in vitro. However, this homeostatic mechanism in injured site is overwhelmed, leading to the development of foamy macrophages and lipid plaque in the lesion site. The persistence of these cells indicates a pro-inflammatory environment, associated with enhanced neurotoxicity and impaired wound healing. These foamy macrophages have poor capacity to phagocytose apoptotic neutrophils resulting in uningested neutrophils releasing their toxic contents and further tissue damage. In conclusion, these data demonstrate for the first time that myelin debris generated in injured spinal cord modulates macrophage activation. Lipid accumulation following macrophage phenotype switch contributes to SCI pathology. GLIA 2014. © 2014 Wiley Periodicals, Inc.
    Glia 04/2015; 63(4). DOI:10.1002/glia.22774 · 6.03 Impact Factor
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    ABSTRACT: Stem cell therapies have had tremendous potential application for many diseases in recent years. However, the tumorigenic properties of stem cells restrict their potential clinical application; therefore, strategies for reducing the tumorigenic potential of stem cells must be established prior to transplantation. We have demonstrated that syngeneic transplantation of embryonic stem cells (ESCs) provokes an inflammatory response that involves the rapid recruitment of bone marrow-derived macrophages (BMDMs). ESCs are able to prevent mature macrophages from macrophage colony-stimulating factor (M-CSF) withdrawal-induced apoptosis, and thus prolong macrophage lifespan significantly by blocking various apoptotic pathways in an M-CSF-independent manner. ESCs express and secrete IL-34, which may be responsible for ESC-promoted macrophage survival. This anti-apoptotic effect of ESCs involves activation of extracellular signal-regulated kinase (ERK)1/2 and PI3K/Akt pathways and thus, inhibition of ERK1/2 and PI3K/AKT activation decreases ESC-induced macrophage survival. Functionally, ESC-treated macrophages also showed a higher level of phagocytic activity. ESCs further serve to polarize BMDMs into M2-like macrophages that exhibit most tumor-associated macrophage phenotypic and functional features. ESC-educated macrophages produce high levels of arginase-1, Tie-2, and TNF-α, which participate in angiogenesis and contribute to teratoma progression. Our study suggests that induction of M2-like macrophage activation is an important mechanism for teratoma development. Strategies targeting macrophages to inhibit teratoma development would increase the safety of ESC-based therapies, inasmuch as the depletion of macrophages completely inhibits ESC-induced angiogenesis and teratoma development.
    Frontiers in Immunology 07/2014; 5:275. DOI:10.3389/fimmu.2014.00275
  • Xin Chen · Chuan Cai · Jing Liu · Li Wen · Xi Wang · Yin Ding ·
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    ABSTRACT: It is well‑known that estrogen-related receptor α (ERRα) affects numerous metabolic pathways and biological functions in the body, although the function of ERRα in the mandibular condylar chondrocytes (MCCs) of the temporomandibular joint remains unclear. The aim of the present study was to investigate the effect of ERRα on the biological characteristics of MCCs in female rats. Immunofluorescent staining was used to observe the expression level and distribution of ERRα in MCCs and tissues. Quantitative polymerase chain reaction (qPCR) was performed to detect the impact of estrogen intervention on the biological characteristics of female rat MCCs and ERRα expression levels. Liposome transfection and XCT‑790 were used to overexpress and inhibit ERRα expression, respectively, and then qPCR was performed to detect changes in the biological characteristics of MCCs. ERRα expression was detected in the nucleus and cytoplasm of rat MCCs. 17‑β estradiol (E2) (10‑8 M) increased the mRNA and protein expression levels of ERRα, Sox9, GDF‑5 and aromatase during in vitro MCC cultivation. In addition, E2 affected MCC proliferation through the regulation of ERRα expression levels. Overexpression of ERRα positively regulated the mRNA and protein expression levels of Sox9 and GDF‑5, but did not exhibit a significant effect on the mRNA and protein expression levels of aromatase and Col2a1. In conclusion, ERRα exhibited an important regulatory role in the proliferation and differentiation of female Sprague‑Dawley rat MCCs in vitro through regulating Sox9 and GDF-5.
    Molecular Medicine Reports 05/2014; 10(1). DOI:10.3892/mmr.2014.2210 · 1.55 Impact Factor
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    ABSTRACT: Objective To reveal the role of bone marrow-derived mesenchymal stem cells (BMSCs) in the development of osteoporosis by comparing the differences in monocyte chemoattractant protein-1 (MCP-1) expression and T cells' migration and apoptosis induced by BMSCs from ovariectomy (OVX) group and sham group. Methods OVX was performed on C57BL/6 mice to establish the animal models of osteoporosis. Osteoporosis was confirmed by micro-CT. The expression of MCP-1 between OVX group and sham group was examined by ELISA; after exogenous estrogen of different concentrations were given to stimulate BMSCs from OVX group, the expression of MCP-1 was observed again by ELISA. Through co-culturing of BMSCs and T cells, the change of T cells' migration and apoptosis capacity induced by BMSCs was compared between OVX group and sham group. And also, we observed the effects of exogenous estrogen of different concentrations on the T cells' migration and apoptosis capacity. Results In animal models of osteoporosis induced by estrogen deficiency, BMSCs had a declined inducing effect on the capacity of T cell migration and apoptosis and expressed a decreased level of migration-related gene MCP-1. After the stimulation of estrogen of certain concentration, the declining tendency was revised to some extent. Conclusion Through expressing MCP-1, BMSCs could regulate the capacity of T cell migration and apoptosis, thus leading to the development of osteoporosis.
    Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 01/2014; 30(1):19-22.
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    ABSTRACT: Objective: To investigate the therapeutic effects of bone marrow-derived mesenchymal stem cells (BMSCs) from C57BL/6 mice on estrogen deficiency induced osteoporosis. Methods: Mouse models of estrogen deficiency induced osteoporosis were set up through ovariectomy (OVX) operation and sham operation group was set up as controls. BMSCs were injected via caudal veins. Micro-CT scanning of the femurs was conducted to detect the therapeutic effects of BMSCs. ELISA was used to test the expression level of TNF-α in serum before and after the injection of BMSCs. In the meantime, T cell apoptosis was also tested by flow cytometry combined with FITC-annexin V/7-amino actimycin D staining. Results: Compared with the sham operation group, the trabecular volume (BV/TV), bone mineral density (BMD) and trabecular number (Tb.N/mm) of osteoporosis mice set up by OVX were reduced significantly, and serum TNF-α was up-regulated a little. After the injection of BMSCs, the BV/TV, Tb.Th, Tb.N and T cell apoptosis in the osteoporosis mice increased, and the level of TNF-α decreased. Conclusion: With the ability of immunoregulation, BMSCs might play a critical role in treating estrogen deficiency induced osteoporosis.
    Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 12/2013; 29(12):1267-71.
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) is a highly conserved and evolutionarily ancient mediator with pleiotropic effects. Recent studies demonstrated that the receptors of MIF, including CD44, CXCR2, CXCR4 and CD74, are expressed in the neural stem/progenitor cells (NSPCs). The potential regulatory effect of MIF on NSPCs proliferation and neuronal differentiation, however, is largely unknown. Here, we investigated the effect of MIF on NSPC proliferation and neuronal differentiation, and further examined the signal pathway by which MIF transduced these signal effects in mouse NSPCs in vitro. The results showed that both Ki67-positive cells and neurosphere volumes were increased in a dose-dependent manner following MIF treatment. Furthermore, the expression of nuclear β-catenin was significantly stronger in MIF-stimulated groups than that in control groups. Conversely, administration of IWR-1, the inhibitor of Wnt/β-catenin pathway, significantly inhibited the proliferative effect of MIF on NSPCs. Immunostaining and Western blot further indicated that doublecortin (DCX) and Tuj 1, two neuronal markers, were evidently increased with MIF stimulation during NSPC differentiation, and there were more Tuj1-positive cells migrated out from neurospheres in MIF-stimulated groups than those in control groups. During NSPC differentiation, MIF increased the activity of β-galactosidase that responds to Wnt/β-catenin signaling. Wnt1 and β-catenin proteins were also up-regulated with MIF stimulation. Moreover, the expression of DCX and Tuj 1 was inhibited significantly by IWR-1. Taken together, the present study indicated that MIF enhances NSPC proliferation and promotes the neuronal differentiation, by activating Wnt/β-catenin signal pathway. The interaction between MIF and Wnt/β-catenin signal pathway may play an important role in modulating NSPC renewal and fate during brain development.
    International journal of biological sciences 11/2013; 9(10):1108-1120. DOI:10.7150/ijbs.7232 · 4.51 Impact Factor
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    ABSTRACT: The reconstruction of large bony defects remains a clinical challenge, and angiogenesis and neovascularisation are being given more attention in bone tissue engineering. In this study we cocultured peripheral blood CD34+ cells (PB-CD34+ cells), an endothelial progenitor cell/haematopoietic stem cell-enriched population, with bone marrow-derived mesenchymal stem cells (MSC) to investigate their potential for bony regeneration. Cocultured cells showed better osteogenic differentiation than MSC alone in vitro. The cocultured cells and MSC sheets were also composited with hydroxyapatite and implanted in calvarial critical-size defects in rabbits. The rabbits were killed before microcomputed tomographic (MicroCT) and histological analysis. The results showed that cocultured cell composites had promoted bony regeneration more efficiently by 8 weeks after implantation. Our results indicate that the coculture of PB-CD34+ cells and MSC increases bony regeneration in calvarial critical-size defects in rabbits, and provide a new promising therapeutic strategy to aid skeletal healing.
    British Journal of Oral and Maxillofacial Surgery 11/2013; 52(2). DOI:10.1016/j.bjoms.2013.10.004 · 1.08 Impact Factor
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    ABSTRACT: Objective: To investigate the difference in the therapeutic effects of bone marrow-derived mesenchymal stem cells (BMSCs) of mice from ovariectomy (OVX) group and sham group in treating colitis, and then further study the differences of Fas/FasL expression and downstream T cell migration and apoptosis between the two groups. Methods: The osteoporosis animal models were set up by ovariectomy in C57BL6 mice. Meanwhile, 3% dextran sulfate sodium (DSS) was administered for inducing colitis. We compared the therapeutic effects of BMSCs from OVX and sham groups in treating colitis, in addition, detected the expression of Fas/FasL in BMSCsby means of RT-PCR and Western blotting. The ability of BMSCs from the two groups of inducing T cell migaration and apoptosis was also detected. Results: Compared with the sham group, BMSCs from OVX mice expressed a lower level of Fas/FasL and displayed a decreased ability of inducing T cell migration and apoptosis, thus leading to an inferior therapeutic effect in treating colitis in animal models. Conclusion: Fas/FasL expression of BMSCs from the OVX mice is down regulated, thus leading to a decrease of the migration and apoptosis for T cells from mouse colitis.
    Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 10/2013; 29(10):1028-1031.
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    ABSTRACT: Background: Cleft lip in the presence or absence of a cleft palate is a major public health problem. However, few studies have been published concerning the soft-tissue morphology of cleft lip infants. Currently, obtaining reliable three-dimensional (3D) surface models of infants remains a challenge. The aim of this study was to investigate a new way of capturing 3D images of cleft lip infants using a structured light scanning system. In addition, the accuracy and precision of the acquired facial 3D data were validated and compared with direct measurements. Study design: Ten unilateral cleft lip patients were enrolled in the study. Briefly, 3D facial images of the patients were acquired using a 3D scanner device before and after the surgery. Fourteen items were measured by direct anthropometry and 3D image software. The accuracy and precision of the 3D system were assessed by comparative analysis. Results: The anthropometric data obtained using the 3D method were in agreement with the direct anthropometry measurements. All data calculated by the software were 'highly reliable' or 'reliable', as defined in the literature. The localisation of four landmarks was not consistent in repeated experiments of inter-observer reliability in preoperative images (P<0.05), while the intra-observer reliability in both pre- and postoperative images was good (P>0.05). Conclusions: The structured light scanning system is proven to be a non-invasive, accurate and precise method in cleft lip anthropometry.
    Journal of Plastic Reconstructive & Aesthetic Surgery 05/2013; 66(8). DOI:10.1016/j.bjps.2013.04.007 · 1.42 Impact Factor
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    ABSTRACT: Recently, it has been reported that the orphan nuclear receptor estrogen-related receptor α (ERRα) is involved in the osteogenic differentiation of mesenchymal stem cells (MSCs). Moreover, ERRα has been identified as a novel therapeutic target for treating osteoporosis and other bone diseases. Human periodontal ligament tissue-derived mesenchymal stem cells (hPDLSCs) have recently been used in stem cell-mediated therapies because of their multipotency, particularly toward osteogenic differentiation. However, it is still unclear whether ERRα can regulate the osteogenic differentiation of hPDLSCs. In the present study, we investigated the role of ERRα in the osteogenic differentiation of hPDLSCs in vitro. We isolated hPDLSCs and confirmed their capacity for multipotent differentiation. Furthermore, we examined ERRα expression in hPDLSCs by RT-PCR and immunocytochemistry. We found that the expression of ERRα mRNA was significantly increased during the late stage of osteogenic differentiation of hPDLSCs. Moreover, transfection of recombinant lentiviral-mediated miRNA targeting ERRα significantly suppressed ALP activity, mineralization capacity, and the mRNA expression of osteogenesis-related genes (ALP, OCN, RUNX2 and OPN) in hPDLSCs. Our results indicate that ERRα may promote the osteogenic differentiation of hPDLSCs in vitro.
    International Journal of Molecular Medicine 03/2013; 31(5). DOI:10.3892/ijmm.2013.1305 · 2.09 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) remains highly fatal, highlighting the need for improved understanding of signal pathways that can lead to the development of new therapeutic regimens targeting common molecular pathways shared across different AML subtypes. Here we demonstrate that Astrocyte elevated gene-1 (AEG-1) is one of such pathways, involving in cell cycle and apoptosis regulation and contributing to enhanced proliferation and chemoresistance in HL-60 and U937 AML cells. The pleiotropic effects of AEG-1 on AML were found to correlate with two novel target genes, Aurora kinase A (AURKA) and Akt1. Down-regulation of AEG-1 by short-hairpin RNA (shRNA) could not only decrease AURKA expression both on mRNA and protein levels but also decrease the levels of pAkt473 and pAkt308(the active forms of phosphorylated Akt), similar effect as using AURKA inhibitor Tozasertib (VX680). Furthermore, the AEG-1 shRNA-induced malignant phenotype changes could be mitigated by forced overexpression of AURKA through increased Akt1 activation and phosphorylation in AML cells. On the other hand, although exogenous expression of AEG-1 could increase both AURKA and Akt expression levels the simultaneous use of AURKA inhibitor Tozasertib blocked AEG-1's role of up-regulation of Akt expression in ECV304 cells, suggesting that AURKA might be a key mediator of AEG-1 in regulating Akt activation, and a key effector of AEG-1 in maintaining the malignant state of AML. Moreover, knockdown AEG-1 expression also changed the expression levels of PTEN, survivin and stathmin, the genes that have been reported to be involved in the development of several other malignant tumors. Our results provide evidence for AEG-1's carcinogenesis role in AML and reveal a novel functional link between AEG-1 and AURKA on Akt1 activation. AEG-1 can be an important candidate as a drug design target within AURKA signal pathway for more specific killing of AML cells while sparing normal cells.
    Cellular Signalling 03/2013; 25(6). DOI:10.1016/j.cellsig.2013.03.001 · 4.32 Impact Factor
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    ABSTRACT: Inflammatory cytokines, especially TNF-α, have been shown to inhibit osteogenic differentiation of mesenchymal stem cells (MSCs) and bone formation in estrogen deficiency-induced osteoporosis, but the mechanism responsible remains poorly understood. MicroRNAs (miRNAs) have been shown to regulate MSC differentiation. Here, we identified a novel mechanism that TNF-α suppressing the functional axis of a key miRNA(miR-21) contributes to estrogen deficiency-induced osteoporosis. In this study, we screened a key miRNA (miR-21) that was significantly down-regulated in MSCs derived from estrogen deficiency-induced osteoporosis. The miR-21 was suppressed by TNF-α during the osteogenesis of MSCs. Furthermore, miR-21 was confirmed to promote the osteoblast differentiation of MSCs by repressing Spry1, which can negatively regulate the osteogenic differentiation of MSCs. Up-regulating miR-21 partially rescued TNF-α-impaired osteogenesis of MSCs. Blocking TNF-α ameliorated the inflammatory environment and significantly enhanced bone formation with increased miR-21 expression and suppressed Spry1 expression in ovariectomized (OVX) mice. Our results revealed a novel function for miR-21 and suggested that suppressed miR-21 may contribute to impaired bone formation by elevated TNF-α in estrogen deficiency-induced osteoporosis. This study may indicate a molecular basis for novel therapeutic strategies against osteoporosis and other inflammatory bone diseases. © 2012 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2013; 28(3). DOI:10.1002/jbmr.1798 · 6.83 Impact Factor
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) has critical functions in promoting survival, expansion, and differentiation of neural stem cells (NSCs), but its downstream regulation mechanism is still not fully understood. The role of BDNF in proliferation and differentiation of NSCs through Wnt/β-catenin signaling was studied via cell culture of cortical NSCs, Western blotting, immunocytochemistry, and TOPgal (Wnt reporter) analysis in mice. First, BDNF stimulated NSC proliferation dose dependently in cultured neurospheres that exhibited BrdU incorporation and neuronal and glial differentiation abilities. Second, BDNF effectively enhanced cell commitment to neuronal and oligodendrocytic fates, as indicated by increased differentiation marker Tuj-1 (neuronal marker), CNPase (oligodendrocyte marker), and neuronal process extension. Third, BDNF upregulated expression of Wnt/β-catenin signaling (Wnt1 and free β-catenin) molecules. Moreover, these promoting effects were significantly inhibited by application of IWR1, a Wnt signaling-specific blocker in culture. The TOPgal mouse experiment further confirmed BDNF-triggered Wnt signaling activation by β-gal labeling. Finally, an MEK inhibition experiment showed a mediating role of the microtubule-associated protein kinase pathway in BDNF-triggered Wnt/β-catenin signaling cascades. This study overall has revealed that BDNF might contribute to proliferation and neuronal and oligodendrocytic differentiation of NSCs in vitro, most possibly by triggering the Wnt/β-catenin signaling pathway. Nevertheless, determining the exact cross-talk points at which BDNF might stimulate Wnt/β-catenin signaling pathway in NSC activity requires further investigation. © 2012 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 11/2012; 91(1). DOI:10.1002/jnr.23138 · 2.59 Impact Factor
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    ABSTRACT: Abstract miR-34a was identified as one of the downregulated microRNAs (miRNAs) in human lung cancer. However, the precise biological role of miR-34a in p53 deficient lung cancer cell lines remains largely elusive. In the present study, we aimed to identify the role of miR-34a in the regulation of lung cancer cell proliferation. Using quantitative RT-PCR analysis, we found that miR-34a was highly upregulated in the p53 wild-type A549 human lung cancer cell line when treated with the DNA damaging agent adriamycin (ADR), but not in the SBC-5 cells harboring mutated p53. Transient introduction of miR-34a into A549 and SBC-5 cell lines caused complete suppression of cell proliferation and induced the cell cycle arrested at the G(1) phase. When we knockdown the miR-34a downstream target-Sitr1- using the small-interfering RNA, there was also a cell growth inhibition in both cell lines though not as much as miR-34a did. Moreover, we demonstrated that pretransfection of miR-34a could increase the sensitivity of both lung cancer cell lines to cisplatin (DDP), and this could be reverted by the miR-34a inhibitor. Moreover, when cells pretreated with siR-Sirt1, they are more sensitive to DDP than the control pretreated cells as well. We thus hypothesize the miR-34a/Sirt1 cascade involved with p53-independent functions. Overall, in this study, we found the proliferation inhibition function of miR-34a in vitro in lung cancer cell lines is p53 independent, and also demonstrated the combination therapeutic potential of miR-34a and DDP in lung cancer cell lines.
    Cancer Biotherapy & Radiopharmaceuticals 10/2012; 28(1). DOI:10.1089/cbr.2012.1218 · 1.78 Impact Factor
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    ABSTRACT: The bone marrow-derived mesenchymal stem cells or mesenchymal stromal cells (MSCs), with pluripotent differentiation capacity, present an ideal source for cell transplantation or tissue engineering therapies, but exact understanding of regulating mechanism underling MSC proliferation and differentiation remains a critical issue in securing their safe and efficient clinical application. This review outlines current knowledge regarding MSC cell surface biomarkers and molecular mechanisms of MSC differentiation and proliferation with emphasis on Wnt/β-catenin signaling, Notch signaling pathway, bone morphogenesis proteins and various growth factors functioning in regulation of differentiation and proliferation of MSCs. Possible relation of oncogene and immunosuppressive activities of MSCs with tumorigenicity or tumor generation is also addressed for safe translational clinical application. Fast increase of MSC knowledge and techniques has led to some successful clinical trials and helped devising new tissue engineering therapies for bone and cartilage diseases that severely afflict human health. Production of adult MSC-derived functional neurons can further extend their therapeutic application in nerve injury and neurodegenerative diseases. It is promising that MSCs shall overcome ethical and immunorejection problems appeared in human embryonic stem cells, and specific molecular targeting manipulation may result in practical MSC therapy for personalized treatment of various diseases in the regeneration medicine.
    Current drug targets 04/2012; 13(4):561-71. DOI:10.2174/138945012799499749 · 3.02 Impact Factor
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    ABSTRACT: Although stem cell therapy holds promise as a potential treatment in a number of diseases, the tumorigenicity of embryonic stem cells (ESC) and induced pluripotent stem cells remains a major obstacle. In vitro predifferentiation of ESCs can help prevent the risk of teratoma formation, yet proliferating neural progenitors can generate tumors, especially in the presence of immunosuppressive therapy. In this study, we investigated the effects of the microenvironment on stem cell growth and teratoma development using undifferentiated ESCs. Syngeneic ESC transplantation triggered an inflammatory response that involved the recruitment of bone marrow (BM)-derived macrophages. These macrophages differentiated into an M2 or angiogenic phenotype that expressed multiple angiogenic growth factors and proteinases, such as macrophage migration inhibitory factor (MIF), VEGF, and matrix metalloproteinase 9, creating a microenvironment that supported the initiation of teratoma development. Genetic deletion of MIF from the host but not from ESCs specifically reduced angiogenesis and teratoma growth, and MIF inhibition effectively reduced teratoma development after ESC transplantation. Together, our findings show that syngeneic ESC transplantation provokes an inflammatory response that involves the rapid recruitment and activation of BM-derived macrophages, which may be a crucial driving force in the initiation and progression of teratomas.
    Cancer Research 03/2012; 72(11):2867-78. DOI:10.1158/0008-5472.CAN-11-3247 · 9.33 Impact Factor
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    ABSTRACT: This study focused on the characterization of stem cells from human exfoliated deciduous teeth (SHED) in comparison with dental pulp stem cells (DPSCs) to certify SHED as a key element in tissue engineering. In the present study, SHED and DPSCs were assayed for their cell surface antigens and proliferation by measuring the cell cycles, growth rates, Ki67-positive efficiencies, and colony-forming units (CFUs). The evaluation of multi-differentiation was performed using alizarin red and oil red O and real-time PCR in vitro. The mineralization capability of the cells was examined in vivo by implanting with ceramic bovine bone (CBB) into subcutaneous of immunocompromised mice for 8weeks. A three-dimensional pellet cultivation system is proposed for SHED and DPSCs to recreate the biological microenvironment that is similar to that of a regenerative milieu. SHED showed a higher proliferation rate and differentiation capability in comparison with DPSCs in vitro, and the results of the in vivo transplantation suggest that SHED have a higher capability of mineralization than the DPSCs. The mRNA expression levels of inflammatory cytokines, including matrix metalloproteinase-1 (MMP1), tissue inhibitors of metalloproteinase-1 (TIMP1), matrix metalloproteinase-2 (MMP2), tissue inhibitors of metalloproteinase-2 (TIMP2) and interleukin-6 (IL-6) were higher in SHED than that in DPSCs. In addition, the expression levels of Col I and proliferating cell nuclear antigen (PCNA) in SHED sheets were significantly higher than those in DPSCs sheets. This study systematically demonstrated the differences in the growth and differentiation characteristics between SHED and DPSCs. Consequently, SHED may represent a suitable, accessible and potential alternative source for regenerative medicine and therapeutic applications.
    Archives of oral biology 03/2012; 57(9):1231-40. DOI:10.1016/j.archoralbio.2012.02.014 · 1.74 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is a severe deliberating neurological disease caused by progressive degenerative death of dopaminergic neurons in the substantia nigra of midbrain. While cell replacement strategy by transplantation of neural stem cells and inducement of dopaminergic neurons is recommended for the treatment of PD, understanding the differentiation mechanism and controlled proliferation of grafted stem cells remain major concerns in their clinical application. Here we review recent studies on molecular signaling pathways in regulation of dopaminergic differentiation and proliferation of stem cells, particularly Wnt/beta-catenin signaling in stimulating formation of the dopaminergic phenotype, Notch signaling in inhibiting stem cell differentiation, and Sonic hedgehog functioning in neural stem cell proliferation and neuronal cell production. Activation of oncogenes involved in uncontrolled proliferation or tumorigenicity of stem cells is also discussed. It is proposed that a selective molecular manipulation targeting strategy will greatly benefit cell replacement therapy for PD by effectively promoting dopaminergic neuronal cell generation and reducing risk of tumorigenicity of in vivo stem cell applications.
    CNS & neurological disorders drug targets 06/2011; 10(4):517-28. DOI:10.2174/187152711795563912 · 2.63 Impact Factor
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    ABSTRACT: Several conserved neutralizing epitopes have been identified in the HIV Env protein and among these, the MPER of gp41 has received great attention and is widely recognized as a promising target. However, little success has been achieved in eliciting MPER-specific HIV neutralizing antibodies by a number of different vaccine strategies. We investigated the ability of HA/gp41 chimeric protein-based vaccines, which were designed to enhance the exposure of the MPER in its native conformation, to induce MPER-specific HIV neutralizing antibodies. In characterization of the HA/gp41 chimeric protein, we found that by mutating an unpaired Cys residue (Cys-14) in its HA1 subunit to a Ser residue, the modified chimeric protein HA-C14S/gp41 showed increased reactivity to a conformation-sensitive monoclonal antibody against HA and formed more stable trimers in VLPs. On the other hand, HA-C14S/gp41 and HA/gp41 chimeric proteins expressed on the cell surfaces exhibited similar reactivity to monoclonal antibodies 2F5 and 4E10. Immunization of guinea pigs using the HA-C14S/gp41 DNA or VLP vaccines induced antibodies against the HIV gp41 as well as to a peptide corresponding to a segment of MPER at higher levels than immunization by standard HIV VLPs. Further, sera from vaccinated guinea pigs were found to exhibit HIV neutralizing activities. Moreover, sera from guinea pigs vaccinated by HA-C14S/gp41 DNA and VLP vaccines but not the standard HIV VLPs, were found to neutralize HIV pseudovirions containing a SIV-4E10 chimeric Env protein. The virus neutralization could be blocked by a MPER-specific peptide, thus demonstrating induction of MPER-specific HIV neutralizing antibodies by this novel vaccine strategy. These results show that induction of MPER-specific HIV neutralizing antibodies can be achieved through a rationally designed vaccine strategy.
    PLoS ONE 05/2011; 6(5):e14813. DOI:10.1371/journal.pone.0014813 · 3.23 Impact Factor

Publication Stats

856 Citations
129.21 Total Impact Points


  • 2010-2015
    • Rutgers, The State University of New Jersey
      • • W.M. Keck Center for Collaborative Neuroscience
      • • Department of Cell Biology and Neuroscience
      Нью-Брансуик, New Jersey, United States
  • 2003-2015
    • Fourth Military Medical University
      • • Department of Orthodontics
      • • Department of Hematology
      • • Institute of Neurosciences
      Xi’an, Liaoning, China
  • 2013-2014
    • Zhengzhou University
      Cheng, Henan Sheng, China
    • Chongqing Medical University
      Ch’ung-ch’ing-shih, Chongqing Shi, China