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Kevin J Kim,
Jamie Wang,
Xiaohong Xu,
Sharon Wu,
Wei Zhang,
Zhen Qin,
Fenglan Wu, Ailian Liu,
Yonggang Zhao,
Haiyan Fang,
Mary Zhu,
Jing Zhao,
Zhong Zhong
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ABSTRACT: The authors designed a chemical genomics screen with the aim of understanding genes and pathways that modulate neural stem/precursor cell differentiation. Multipotent mouse neural precursor cells isolated from cortices of embryonic day 12 (E12) embryos were subjected to spontaneous differentiation triggered by growth factor withdrawal. A quantitative whole-well immunofluorescence assay was set up to screen tool compound sets to identify small molecules with potent, dose-dependent, and reproducible effects on increasing neural stem cell differentiation toward neuronal lineage. Among the pro-neuronal compounds, kinase inhibitors were shown to exert pro-neuronal effect via a signaling pathway associated with the kinase. The global effect of hit compounds on modulating neuronal differentiation was confirmed by an in vivo mouse study and human neural stem cells culture. This study demonstrates that a phenotypic assay using cell type-specific antibody markers can be used for a large-scale compound screen to discover targets and pathways with impacts on differentiation of lineage-restricted precursor cells toward specific lineages.
Journal of Biomolecular Screening 09/2011; 17(2):129-39. · 2.05 Impact Factor
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Wei Cao,
Yiqing Yang,
Zhengyi Wang, Ailian Liu,
Lei Fang,
Fenglan Wu,
Jian Hong,
Yufang Shi,
Stewart Leung,
Chen Dong,
Jingwu Z Zhang
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ABSTRACT: Neural progenitor cell (NPC) therapy is considered a promising treatment modality for multiple sclerosis (MS), potentially acting through neural repair. Here, we showed that intravenous administration of NPCs ameliorated experimental autoimmune encephalomyelitis (EAE) by selectively inhibiting pathogenic T helper 17 (Th17) cell differentiation. Leukemia inhibitory factor (LIF) produced by NPCs was responsible for the observed EAE suppression. Through the inducible LIF receptor expression, LIF inhibited the differentiation of Th17 cells in EAE mice and that from MS subjects. At the molecular level, LIF exerted an opposing effect on interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation required for Th17 cell differentiation by triggering a signaling cascade that activated extracellular signal-regulated MAP kinase (ERK) and upregulated suppressor of cytokine signaling 3 (SOCS3) expression. This study reveals a critical role for LIF in regulating Th17 cell differentiation and provides insights into the mechanisms of action of NPC therapy in MS.
Immunity 08/2011; 35(2):273-84. · 21.64 Impact Factor
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ABSTRACT: To determine the possible involvement of neutrophils in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), we examined their infiltration pattern during the course of MOG35-55-induced EAE in the C57BL/6 mice. Using immunohistochemistry and flow cytometry, we found that the number of neutrophils was significantly increased during onset of disease, remained high at the peak stage and dramatically declined thereafter. Moreover, dual labeling provided anatomical evidence of a prominent accumulation of neutrophils in the center and vicinity of lesion areas of demyelination, axonal loss or axonal degeneration at early stages of EAE. These observations provide evidence that neutrophils are one of the major sources of inflammatory cells to initiate EAE, which suggest that neutrophils may contribute to demyelination and axonal degeneration in the acute phase of EAE and play a greater role than previously thought in the pathogenesis of EAE.
Histochemie 03/2010; 133(3):313-22. · 2.59 Impact Factor
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Xuebin Liu,
Stewart Leung,
Chunxia Wang,
Zhu Tan,
Ji Wang,
Taylor B Guo,
Lei Fang,
Yonggang Zhao,
Bing Wan,
Xia Qin,
Limin Lu,
Runsheng Li,
Heng Pan,
Mingjuan Song, Ailian Liu,
Jian Hong,
Hongtao Lu,
Jingwu Z Zhang
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ABSTRACT: Interleukin-7 receptor (IL-7R) is genetically associated with susceptibility to multiple sclerosis. Here we describe that IL-7 is essential for survival and expansion of pathogenic T helper type 17 (T(H)17) cells in experimental autoimmune encephalomyelitis (EAE). IL-7 directly expanded effector T(H)17 cells in EAE and human T(H)17 cells from subjects with multiple sclerosis, whereas it was not required for T(H)17 differentiation. IL-7R antagonism rendered differentiated T(H)17 cells susceptible to apoptosis through the inhibition of Janus kinase-signal transducer and activator of transcription-5 (JAK-STAT5) pathway and altered expression of the prosurvival protein Bcl-2 and the proapoptotic protein Bax, leading to decreased severity of EAE. In contrast, T(H)1 and regulatory T (T(reg)) cells were less susceptible to or not affected by IL-7R antagonism in vivo. The selectivity was attributable to minimal expression of IL-7Ralpha in T(reg) cells and correlated with a high level of Socs1 (encoding suppressor of cytokine signaling-1) expression in T(H)1 cells. The study reveals a unique, previously undescribed role of IL-7-IL-7R in T(H)17 cell survival and expansion and has implications in the treatment of autoimmune disease.
Nature medicine 02/2010; 16(2):191-7. · 27.14 Impact Factor
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ABSTRACT: The exact role of adult thymus in autoimmune disease state is poorly understood. We show here that thymus regulated experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, as evidenced by loss of spontaneous recovery in thymectomized EAE mice. There was progressive enrichment for CD4 single-positive Foxp3(+) regulatory T cells in thymocytes during the course of EAE and they suppressed the disease when adoptively transferred. Thymus was shown to undergo an active process characterized by accelerated differentiation and proliferation of regulatory T (Treg) cells through a mechanism involving increased expression of IL-7 in stromal cells and dynamic expression of IL-7 receptor in thymic Treg cells. This process preceded EAE recovery and selectively affected Treg over non-Treg cells in the thymus, leading to increased output of thymic Treg cells and self-regulation of EAE. The study reveals a novel role of thymus in self-regulation of autoimmune condition.
The Journal of Immunology 11/2009; 183(10):6135-44. · 5.79 Impact Factor
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ABSTRACT: Berbamine (BM) is an herbal compound derived from Berberis vulgaris L commonly used in traditional Chinese medicine. In this study, we show that BM has potent anti-inflammatory properties through novel regulatory mechanisms, leading to reduced encephalitogenic T cell responses and amelioration of experimental autoimmune encephalomyelitis (EAE). The treatment effect of BM was attributable to its selective inhibitory effect on the production and action of IFN-gamma in CD4(+) T cells, which was mediated through altered STAT4 expression in T cells. BM was found to up-regulate SLIM, a ubiquitin E3 ligase for STAT4, and promote STAT4 degradation, resulting in markedly decreased IFN-gamma production in CD4(+) T cells in EAE mice. Regulation of IFN-gamma by BM had profound anti-inflammatory actions through its effect on both CD4(+) T cells and APCs. BM-treated APCs exhibited reduced stimulatory function as a result of altered expression of PD-L1, CD80, and CD86 in treated mice. The treatment effect of BM in EAE was directly related to its action on IFN-gamma, and was abolished in IFN-gamma knockout mice. The study also confirmed that BM was able to inhibit NFAT translocation through effecting calcium mobilization in lymphocytes. However, this effect was not directly responsible for the treatment efficacy of BM in EAE. The study has important implications in our approaches to evaluating the utility of natural compounds in drug discovery and to probing the role of cytokine network in the development of autoimmune conditions.
The Journal of Immunology 08/2008; 181(2):1491-8. · 5.79 Impact Factor
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ABSTRACT: Inherited deficiencies in critical components of metabolic pathways are the primary cause of many liver and lysosomal disorders, most of which are incurable. Stem cell transplantation may offer a new type of treatment for these diseases. We have isolated hepatocyte precursors from human fetal livers. These cells were highly proliferative in vitro in media with or without serum. Expanded hepatocyte precursors expressed endoderm and early hepatocyte markers. The precursors synthesized a large number of molecules related to human metabolic diseases and released some of them into the environment. In a homing test, these cells migrated preferentially into the liver. When transplanted into fetal sheep liver, they incorporated into the liver tissue and differentiated into hepatocytes. Transplantation of the liver precursors to alpha-l-iduronidase-deficient mice partially corrected the enzyme deficiency. Data from these studies suggest that in vitro expanded human liver precursor cells are a potential cell source for the treatment of liver- and lysosome-related disorders.
Differentiation 01/2008; 75(10):928-38. · 2.81 Impact Factor
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ABSTRACT: Ethyl 2-[4-(12-beta-artemisininoxy)]phenoxylpropionate (SM933) is a novel derivative of artemisinin, an herbal compound approved for the treatment of malaria. In this study, we show that SM933 has unique anti-inflammatory properties through regulation of signaling pathways, leading to amelioration of experimental autoimmune encephalomyelitis. The anti-inflammatory properties of SM933 were characterized by inhibition of encephalitogenic T cell responses that were altered to exhibit a Th2 immune deviation and reduced activity and concentration of NO and inducible NO synthase. The observed effect of SM933 was mediated through regulatory mechanisms involving the NFkappaB and the Rig-G/JAB1 signaling pathways. SM933 was found to inhibit the activity of NFkappaB by up-regulating IkappaB, which accounted for various down-stream anti-inflammatory actions. Furthermore, it up-regulated Rig-G through the action of IFN-alpha and prevented JAB1, a master cell cycle regulator, from entering the nucleus to promote p27 degradation, resulting in down-regulation of CDK2 and cyclin A and cell cycle progression. Regulation of the Rig-G/JAB1 pathway by SM933 led to altered cell cycle activity of encephalitogenic T cells as a result of its selective effect on activated, but not resting, T cells. The study indicates that SM933 is a novel anti-inflammatory agent acting through defined signaling mechanisms and provides regulatory mechanisms required for effective drug targeting in treatment of autoimmune disease and inflammation.
The Journal of Immunology 12/2007; 179(9):5958-65. · 5.79 Impact Factor
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Bin Chen,
Jianjun Shi,
Junke Zheng,
Ying Chen,
Kai Wang,
Qingzhang Yang,
Xuejin Chen,
Zhuqing Yang,
Xiaofei Zhou,
Youming Zhu,
Jianxin Chu, Ailian Liu,
Hui Z Sheng
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ABSTRACT: In previous studies, progenitor embryoid body-derived (EBD) cells have been derived from human embryonic germ cells. These cells express lineage markers of three primary germ layers, although their potential to produce true fetal cells of various types has yet to be tested. To this end, we have transplanted EBD cells into the fetal sheep liver. We show that these cells respond appropriately to environmental cues and give rise to hepatocytes and well-structured bile ducts. These results suggest that EBD cells are relatively uncommitted early progenitors capable of effective incorporation and differentiation in vivo. The ability to generate functional liver cells makes EBD cells potentially useful for cell therapy.
Differentiation 07/2007; 75(5):350-9. · 2.81 Impact Factor
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ABSTRACT: Chronic activity of hepatitis B is thought to involve aberrant immune tolerance of unknown mechanism. In this study, we examined the role of CD4(+)CD25(+)Foxp3(+) regulatory T cells in disease activity and viral clearance in hepatitis B. Patients with chronic active hepatitis B (CAH) and asymptomatic HBV carriers (AsC) exhibited a significantly high frequency of CD4(+)CD25(+)Foxp3(+) T cells as opposed to that of controls and resolved HBV infection. These CD4(+)CD25(+) T cells expressed an elevated level of Foxp3 and displayed increased inhibitory activity towards both CD4(+)CD25(-) and CD8(+) effector cells. They were found to accumulate in liver biopsy tissue of CAH patients as opposed to controls. The frequency of CD4(+)CD25(+)Foxp3(+) T cells correlated positively with hepatitis B envelope (HBe) antigen status and serum HBV DNA copy numbers and had a converse relationship with HBe antibody status in patients with CAH and AsC. It was evident that in these patients, the increased frequency of CD4(+)CD25(+)Foxp3(+) T cells was associated with serum levels of transforming growth factor-beta known to promote peripheral conversion of CD4(+)CD25(-) T cells to CD4(+)CD25(+)Foxp3(+) regulatory T cells. The findings provide new insights into the role of CD4(+)CD25(+)Foxp3(+) regulatory T cells in chronic activity and viral clearance in chronic hepatitis B.
International Immunology 03/2007; 19(2):133-40. · 3.41 Impact Factor
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ABSTRACT: T cell activation and function are critically regulated by positive and negative costimulatory molecules. Aberrant expression and function of costimulatory molecules have been associated with persistent activation of self-reactive T cells in autoimmune diseases such as rheumatoid arthritis (RA). In this study, initial analysis of costimulatory molecules led to the unexpected observation that, in addition to CD80, several negative regulators (e.g., CTLA-4, programmed death-1 (PD-1), and PD ligand-1) were overexpressed in synovial T cells and macrophages derived from RA patients as opposed to controls. The expression of CD80 and PD ligand-1 on monocytes could be induced in vitro by IFN-gamma and TNF-alpha that were produced abundantly in RA-derived synovial fluid (SF). Furthermore, the soluble form of negative costimulatory molecules occurred at high concentrations in sera and SF of RA patients and correlated with titers of rheumatoid factor in RA patients. In particular, the levels of soluble PD-1 were found to correlate significantly with those of TNF-alpha in SF derived from RA patients. Detailed characterization of soluble PD-1 revealed that it corresponded to an alternative splice variant (PD-1Deltaex3) and could functionally block the regulatory effect of membrane-bound PD-1 on T cell activation. Our data indicate a novel pathogenic pathway in which overexpression of negative costimulatory molecules to restrict synovial inflammation in RA is overruled by the excessive production of soluble costimulatory molecules.
The Journal of Immunology 01/2007; 177(12):8844-50. · 5.79 Impact Factor
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ABSTRACT: Embryonic stem cells were isolated from rabbit blastocysts derived from fertilization (conventional rbES cells), parthenogenesis (pES cells) and nuclear transfer (ntES cells), and propagated in a serum-free culture system. Rabbit ES (rbES) cells proliferated for a prolonged time in an undifferentiated state and maintained a normal karyotype. These cells grew in a monolayer with a high nuclear/cytoplasm ratio and contained a high level of alkaline phosphate activity. In addition, rbES cells expressed the pluripotent marker Oct-4, as well as EBAF2, FGF4, TDGF1, but not antigens recognized by antibodies against SSEA-1, SSEA-3, SSEA-4, TRA-1-10 and TRA-1-81. All 3 types of ES cells formed embryoid bodies and generated teratoma that contained tissue types of all three germ layers. rbES cells exhibited a high cloning efficiency, were genetically modified readily and were used as nuclear donors to generate a viable rabbit through somatic cell nuclear transfer. In combination with genetic engineering, the ES cell technology should facilitate the creation of new rabbit lines.
Experimental Cell Research 12/2006; 312(18):3669-82. · 3.58 Impact Factor
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ABSTRACT: IFN-gamma is an important Th1 proinflammatory cytokine and has a paradoxical effect on EAE in which disease susceptibility is unexpectedly heightened in IFN-gamma-deficient mice. In this study, we provide what we believe is new evidence indicating that IFN-gamma is critically required for the conversion of CD4+ CD25- T cells to CD4+ Tregs during EAE. In our study, the added severity of EAE in IFN-gamma knockout mice was directly associated with altered encephalitogenic T cell responses, which correlated with reduced frequency and function of CD4+ CD25+ Foxp3+ Tregs when compared with those of WT mice. It was demonstrated in both human and mouse systems that in vitro IFN-gamma treatment of CD4+ CD25- T cells led to conversion of CD4+ Tregs as characterized by increased expression of Foxp3 and enhanced regulatory function. Mouse CD4+ CD25- T cells, when treated in vitro with IFN-gamma, acquired marked regulatory properties as evidenced by suppression of EAE by adoptive transfer. These findings have important implications for the understanding of the complex role of IFN-gamma in both induction and self regulation of inflammatory processes.
Journal of Clinical Investigation 10/2006; 116(9):2434-41. · 15.39 Impact Factor
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ABSTRACT: To investigate the differences of proliferation capacity and phenotype properties of mesenchymal stem cells (MSCs) derived from bone marrow (BM) of aplastic anemia patients, fetuses and children, MSCs were isolated from BM of patients with aplastic anemia and expanded in vitro; MSCs derived from BM of fetuses and children were used as normal control groups, three sources of MSCs were compared by morphology, in vitro proliferation capacity, phenotype and immunocytochemistry. The results showed that MSCs could be isolated and expanded from aplastic anemia patient BM. MSCs derived from BM of aplastic anemia patients shared a similar morphology and phenotype with derived MSCs from BM of fetuses and children. However, in vitro proliferation capacity of MSCs derived from BM of aplastic anemia patients after 20 population doublings (PD) was significantly lower, compared with MSCs from BM of fetuses and children. BM MSCs derived from children and fetuses proliferated for more than 30 PD. It is concluded that BM MSCs from aplastic anemia patients appears to be normal in phenotype but their proliferation capacity is lower in comparison with control groups.
Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 11/2005; 13(5):832-8.
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Ying Chen,
Zhi Xu He, Ailian Liu,
Kai Wang,
Wen Wei Mao,
Jian Xin Chu,
Yong Lu,
Zheng Fu Fang,
Ying Tang Shi,
Qing Zhang Yang, [......],
Jin Song Li,
Shao Liang Huang,
Xiang Yin Kong,
Yao Zhou Shi,
Zhi Qiang Wang,
Jia Hui Xia,
Zhi Gao Long,
Zhi Gang Xue,
Wen Xiang Ding,
Hui Zhen Sheng
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ABSTRACT: To solve the problem of immune incompatibility, nuclear transplantation has been envisaged as a means to produce cells or tissues for human autologous transplantation. Here we have derived embryonic stem cells by the transfer of human somatic nuclei into rabbit oocytes. The number of blastocysts that developed from the fused nuclear transfer was comparable among nuclear donors at ages of 5, 42, 52 and 60 years, and nuclear transfer (NT) embryonic stem cells (ntES cells) were subsequently derived from each of the four age groups. These results suggest that human somatic nuclei can form ntES cells independent of the age of the donor. The derived ntES cells are human based on karyotype, isogenicity, in situ hybridization, PCR and immunocytochemistry with probes that distinguish between the various species. The ntES cells maintain the capability of sustained growth in an undifferentiated state, and form embryoid bodies, which, on further induction, give rise to cell types such as neuron and muscle, as well as mixed cell populations that express markers representative of all three germ layers. Thus, ntES cells derived from human somatic cells by NT to rabbit eggs retain phenotypes similar to those of conventional human ES cells, including the ability to undergo multilineage cellular differentiation.
Cell Research 09/2003; 13(4):251-63. · 8.19 Impact Factor
