The Experts below are selected from a list of 207 Experts worldwide ranked by ideXlab platform
Yasushi Fujio - One of the best experts on this subject based on the ideXlab platform.
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Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin induced apoptosis through phosphatidylinositol 3 kinase akt phosphorylation and bcl xl caspase 3 interaction
Circulation, 2001Co-Authors: Shinji Negoro, Tadamitsu Kishimoto, Hidemasa Oh, Eiroh Tone, Keita Kunisada, Yasushi Fujio, Kenneth Walsh, Keiko YamauchitakiharaAbstract:Background—We recently reported that the activation of Glycoprotein (Gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results—We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. A...
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Signal transducer and activator of transcription 3 is required for Glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes.
The Journal of biological chemistry, 2000Co-Authors: Masanobu Funamoto, Shinji Negoro, Eiroh Tone, Keita Kunisada, Yasushi Fujio, Hisao Hirota, Tomoaki Osugi, Masahiro Izumi, Kazuyuki Yoshizaki, Kenneth WalshAbstract:Activation of Glycoprotein (Gp) 130 transduces hypertrophic and cytoprotective signals in cardiac myocytes. In the present study, we have demonstrated that signals through Gp130 increase the expression of vascular endothelial growth factor (VEGF) in cardiac myocytes via the signal transducer and activator of transcription (STAT) 3 pathway. After activation of Gp130 with leukemia inhibitory factor (LIF), expression of VEGF mRNA rapidly increased with a peak at 3 h in cultured cardiac myocytes. Cardiotrophin-1 also enhanced VEGF mRNA expression in a dose-dependent manner. VEGF protein production and secretion to the medium were also enhanced by LIF and cardiotrophin-1 but not by interleukin-6. Adenovirus transfer of the dominant-negative form of STAT3 to cultured cardiac myocytes inhibited induction of VEGF expression induced by LIF, but neither PD98059 nor wortmannin was affected. In murine hearts, intravenous administration of LIF augmented expression of VEGF mRNA; however, the hearts of transgenic mice overexpressing dominant-negative STAT3 showed reduced expression of VEGF mRNA that was not induced after LIF stimulation. These data provide the first evidence that a STAT family protein functions as a regulator of angiogenic growth factors and suggest that Gp130/STAT signaling in cardiac myocytes can control vessel growth during cardiac remodeling.
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ACTIVATION OF PHOSPHATIDYLINOSITOL 3-KINASE THROUGH Glycoprotein 130 INDUCES PROTEIN KINASE B AND P70 S6 KINASE PHOSPHORYLATION IN CARDIAC MYOCYTES
The Journal of biological chemistry, 1998Co-Authors: Yasushi Fujio, Tadamitsu Kishimoto, Keita Kunisada, Hisao Hirota, Hideo Matsui, Keiko Yamauchi-takiharaAbstract:Phosphatidylinositol (PI) 3-kinase is known to be activated by cytokine stimulation through different types of receptors to transduce intracellular responses. We have previously reported that leukemia inhibitory factor (LIF) induces the activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein (MAP) kinase pathways through Glycoprotein (Gp) 130 in cardiac myocytes. However, whether PI 3-kinase is involved in regulation of Gp130 signaling and the activation mechanisms by which it associates with other tyrosine-phosphorylated proteins remain unknown. We found that LIF induced the activation of PI 3-kinase in cardiac myocytes. Moreover, JAK1 binds to PI 3-kinase, and LIF stimulation increases the PI 3-kinase activity in JAK1 immunoprecipitates. Activation of MAP kinase and protein kinase B by LIF was attenuated by wortmannin. LIF-induced p70 S6 kinase activation, protein synthesis, and c-fos mRNA expression were inhibited by wortmannin and rapamycin. Both inhibitors failed to appreciably affect the phosphorylation of STAT3. In conclusion, PI 3-kinase is activated with LIF in cardiac myocytes, and JAK1 is found to associate with this enzyme. PI 3-kinase provides a crucial link between Gp130, MAP kinase, protein kinase B, and p70 S6 kinase in cardiac myocytes.
Tadamitsu Kishimoto - One of the best experts on this subject based on the ideXlab platform.
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humanized antihuman il 6 receptor antibody tocilizumab
Handbook of experimental pharmacology, 2008Co-Authors: Norihiro Nishimoto, Tadamitsu KishimotoAbstract:Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune responses and inflammatory reactions. Overproduction of IL-6 has been shown to play a role in inflammatory autoimmune diseases such as rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA) and, therefore, an agent blocking IL-6 actions can be a therapy of these diseases. IL-6 belongs to a cytokine family, which shares the cytokine receptor subunit Glycoprotein (Gp) 130. This family also includes IL-11, oncostatin-M, and leukemia inhibitory factor (LIF). In the IL-6 receptor (IL-6R) system, both a membrane-bound IL-6R and a soluble form of IL-6R are able to mediate IL-6 signals into the cells through the interaction of Gpl30. Tocilizumab is a humanized antihuman IL-6 receptor antibody designed using genetic engineering technology. Tocilizumab recognizes both the membrane-bound and the soluble form IL-6R and specifically blocks IL-6 actions. Tocilizumab is expected to ameliorate the autoimmune inflammatory diseases with IL-6 overproduction and has been clinically developed as a therapeutic agent for RA, systemic-onset and articular types of JIA, Crohn's disease, etc. Tocilizumab has been shown to be effective not only for improving signs and symptoms but also for preventing joint destruction of RA. Immunopharmacology and clinical benefit of tocilizumab in RA is addressed.
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Receptor engagement by viral interleukin-6 encoded by Kaposi sarcoma-associated herpesvirus.
Blood, 2001Co-Authors: Yoshiyasu Aoki, Tadamitsu Kishimoto, Masashi Narazaki, Giovanna TosatoAbstract:Receptor usage by viral interleukin-6 (vIL-6), a virokine encoded by Kaposi sarcoma- associated herpesvirus, is an issue of controversy. Recently, the crystal structure of vIL-6 identified vIL-6 sites II and III as directly binding to Glycoprotein (Gp)130, the common signal transducer for the IL-6 family of cytokines. Site I of vIL-6, however, comprising the outward helical face of vIL-6, where human IL-6 (hIL-6) would interact with the specific alpha-chain IL-6 receptor (IL-6R), is accessible and not occupied by Gp130. This study examined whether this unused vIL-6 surface is available for IL-6R binding. By enzyme-linked immunosorbent assay, vIL-6 bound to soluble Gp130 (sGp130) but not to soluble IL-6R (sIL-6R). Using plasmon surface resonance, vIL-6 bound to sGp130 with a dissociation constant of 2.5 microM, corresponding to 1000-fold lower affinity than that of hIL-6/sIL-6R complex for Gp130. sIL-6R neither bound to vIL-6 nor affected vIL-6 binding to Gp130. In bioassays, vIL-6 activity was neutralized by 4 monoclonal antibodies (mAbs) recognizing a domain within vIL-6 site I, mapped to the C-terminal part of the AB-loop and the beginning of helix B. The homologous region in hIL-6 participates in site I binding to IL-6R. In addition, binding of vIL-6 to sGp130 was interfered with specifically by the 4 neutralizing anti-vIL-6 mAbs. Based on the vIL-6 crystal structure, the vIL-6 neutralizing mAbs map outside the binding interface to Gp130, suggesting that they either produce allosteric changes or block necessary conformational changes in vIL-6 preceding its binding to Gp130. These results document that vIL-6 does not bind IL-6R and suggest that conformational change may be critical to vIL-6 function.
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Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin induced apoptosis through phosphatidylinositol 3 kinase akt phosphorylation and bcl xl caspase 3 interaction
Circulation, 2001Co-Authors: Shinji Negoro, Tadamitsu Kishimoto, Hidemasa Oh, Eiroh Tone, Keita Kunisada, Yasushi Fujio, Kenneth Walsh, Keiko YamauchitakiharaAbstract:Background—We recently reported that the activation of Glycoprotein (Gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results—We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. A...
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Soluble interleukin-6 (IL-6) receptor with IL-6 stimulates megakaryopoiesis from human CD34+ cells through Glycoprotein (Gp) 130 signaling
Blood, 1999Co-Authors: Xingwei Sui, Ryuhei Tanaka, Kenji Muraoka, Kohichiro Tsuji, Yasuhiro Ebihara, Makoto Yoshida, Kaoru Yamada, Kiyoshi Yasukawa, Tetsuya Taga, Tadamitsu KishimotoAbstract:We have recently shown that stimulation of Glycoprotein (Gp) 130, the membrane-anchored signal transducing receptor component of IL-6, by a complex of human soluble interleukin-6 receptor (sIL-6R) and IL-6 (sIL-6R/IL-6), potently stimulates the ex vivo expansion as well as erythropoiesis of human stem/progenitor cells in the presence of stem cell factor (SCF). Here we show that sIL-6R dose-dependently enhanced the generation of megakaryocytes (Mks) (IIbIIIa-positive cells) from human CD34+ cells in serum-free suspension culture supplemented with IL-6 and SCF. The sIL-6R/IL-6 complex also synergistically acted with IL-3 and thrombopoietin (TPO) on the generation of Mks from CD34+ cells, whereas the synergy of IL-6 alone with TPO was barely detectable. Accordingly, the addition of sIL-6R to the combination of SCF + IL-6 also supported a substantial number of Mk colonies from CD34+ cells in serum-free methylcellulose culture, whereas SCF + IL-6 in the absence of sIL-6R rarely induced Mk colonies. The addition of monoclonal antibodies against Gp130 to the suspension and clonal cultures completely abrogated the megakaryopoiesis induced by sIL-6R/IL-6 in the presence of SCF, whereas an anti-TPO antibody did not, indicating that the observed megakaryopoiesis by sIL-6R/IL-6 is a response to Gp130 signaling and independent of TPO. Furthermore, human CD34+ cells were subfractionated into two populations of IL-6R–negative (CD34+ IL-6R−) and IL-6R–positive (CD34+ IL-6R+) cells by fluorescence-activated cell sorting. The CD34+IL-6R− cells produced a number of Mks as well as Mk colonies in cultures supplemented with sIL-6R/IL-6 or TPO in the presence of SCF. In contrast, CD34+ IL-6R+cells generated much less Mks and lacked Mk colony forming activity under the same conditions. Collectively, the present results indicate that most of the human Mk progenitors do not express IL-6R, and that sIL-6R confers the responsiveness of human Mk progenitors to IL-6. Together with the presence of functional sIL-6R in human serum and relative unresponsiveness of human Mk progenitors to IL-6 in vitro, current results suggest that the role of IL-6 may be mainly mediated by sIL-6R, and that the Gp130 signaling initiated by the sIL-6R/ IL-6 complex is involved in human megakaryopoiesis in vivo.
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ACTIVATION OF PHOSPHATIDYLINOSITOL 3-KINASE THROUGH Glycoprotein 130 INDUCES PROTEIN KINASE B AND P70 S6 KINASE PHOSPHORYLATION IN CARDIAC MYOCYTES
The Journal of biological chemistry, 1998Co-Authors: Yasushi Fujio, Tadamitsu Kishimoto, Keita Kunisada, Hisao Hirota, Hideo Matsui, Keiko Yamauchi-takiharaAbstract:Phosphatidylinositol (PI) 3-kinase is known to be activated by cytokine stimulation through different types of receptors to transduce intracellular responses. We have previously reported that leukemia inhibitory factor (LIF) induces the activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein (MAP) kinase pathways through Glycoprotein (Gp) 130 in cardiac myocytes. However, whether PI 3-kinase is involved in regulation of Gp130 signaling and the activation mechanisms by which it associates with other tyrosine-phosphorylated proteins remain unknown. We found that LIF induced the activation of PI 3-kinase in cardiac myocytes. Moreover, JAK1 binds to PI 3-kinase, and LIF stimulation increases the PI 3-kinase activity in JAK1 immunoprecipitates. Activation of MAP kinase and protein kinase B by LIF was attenuated by wortmannin. LIF-induced p70 S6 kinase activation, protein synthesis, and c-fos mRNA expression were inhibited by wortmannin and rapamycin. Both inhibitors failed to appreciably affect the phosphorylation of STAT3. In conclusion, PI 3-kinase is activated with LIF in cardiac myocytes, and JAK1 is found to associate with this enzyme. PI 3-kinase provides a crucial link between Gp130, MAP kinase, protein kinase B, and p70 S6 kinase in cardiac myocytes.
Xinmin Cao - One of the best experts on this subject based on the ideXlab platform.
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Modulation of the interleukin-6 receptor subunit Glycoprotein 130 complex and its signaling by LMO4 interaction.
The Journal of biological chemistry, 2005Co-Authors: Veronica Novotny-diermayr, Baohong Lin, Xinmin CaoAbstract:Abstract The interleukin (IL)-6-type cytokines play major roles in a variety of biological processes by signaling through a common receptor subunit, Glycoprotein (Gp) 130. We performed yeast two-hybrid screening to identify new binding partners of the activated Gp130 and the associated Janus kinases. LMO4, a LIM domain-containing protein that belongs to a family of oncogenes, was identified in this assay. Further studies show that LMO4 associates with Gp130 and Janus kinase1 in several mammalian cell types. It also interacts with protein-tyrosine phosphatase 2 (SHP2) and suppressor of cytokine signaling 3 (SOCS3). The binding domains involved in these interactions were mapped, and the interactions were shown to be in a direct manner by in vitro binding assays. It is likely that LMO4 exists in the Gp130 complex. The cellular localization of LMO4 was detected primarily in the nucleus with a substantial amount also detected in the cytoplasm in several cell types. The effect of LMO4 in IL-6 signaling was subsequently examined. Overexpression of LMO4 enhanced the transcriptional activity and target gene expression of Stat 3 (signal transducers and activators of transcription 3). Consistent with this, silencing LMO4 expression in stable cell lines expressing the small interfering RNA of LMO4 decreased Stat3 activity. Furthermore, the half-life of Gp130 was shortened, and the production of acute phase proteins induced by IL-6 was reduced. Together, our data reveal a positive regulatory role of LMO4 in IL-6 signaling, possibly by acting as a scaffold for stabilization of the Gp130 complex. These studies may open up a link between the oncogenic effect of LMO proteins and their regulatory role in cytokine signaling in general.
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Protein Kinase C δ Associates with the Interleukin-6 Receptor Subunit Glycoprotein (Gp) 130 via Stat3 and Enhances Stat3-Gp130 Interaction
The Journal of biological chemistry, 2002Co-Authors: Veronica Novotny-diermayr, Tong Zhang, Xinmin CaoAbstract:The transcriptional regulation of Stat proteins is controlled through their C-terminal domains, which harbor both a tyrosine phosphorylation site, required for dimerization and subsequent nuclear translocation, and a serine phosphorylation site, required for maximum transcriptional activity. Previously, we reported that protein kinase Cδ (PKCδ) phosphorylates and interacts with Stat3 in an interleukin (IL)-6-dependent manner. In this study, we further characterized this interaction, and investigated the potential role of such an interaction. We show here that the catalytic domain of PKCδ interacts with the Src homology 2 domain and part of the adjacent C-terminal transactivation domain of Stat3. This interaction, which does not seem to involve a classical phosphotyrosine SH2-mediated binding, however, significantly enhances the interaction of Stat3 and the IL-6 receptor subunit Glycoprotein (Gp) 130, which is the initial step for Stat3 activation by IL-6. Expression of a dominant negative PKCδ or depletion of the endogenous PKCδ by phorbol 12-myristate 3-acetate treatment abrogates the association of Stat3 with Gp130. At the same time, PKCδ is recruited to Gp130 via association with Stat3, which may facilitate its phosphorylation on the Gp130 receptor. Finally, we identified Thr-890, a putative PKC phosphorylation site on Gp130, to be critical for the effect of PKCδ. Our data indicate that PKCδ plays important regulatory roles in IL-6 signaling.
Keita Kunisada - One of the best experts on this subject based on the ideXlab platform.
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Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin induced apoptosis through phosphatidylinositol 3 kinase akt phosphorylation and bcl xl caspase 3 interaction
Circulation, 2001Co-Authors: Shinji Negoro, Tadamitsu Kishimoto, Hidemasa Oh, Eiroh Tone, Keita Kunisada, Yasushi Fujio, Kenneth Walsh, Keiko YamauchitakiharaAbstract:Background—We recently reported that the activation of Glycoprotein (Gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results—We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. A...
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Signal transducer and activator of transcription 3 is required for Glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes.
The Journal of biological chemistry, 2000Co-Authors: Masanobu Funamoto, Shinji Negoro, Eiroh Tone, Keita Kunisada, Yasushi Fujio, Hisao Hirota, Tomoaki Osugi, Masahiro Izumi, Kazuyuki Yoshizaki, Kenneth WalshAbstract:Activation of Glycoprotein (Gp) 130 transduces hypertrophic and cytoprotective signals in cardiac myocytes. In the present study, we have demonstrated that signals through Gp130 increase the expression of vascular endothelial growth factor (VEGF) in cardiac myocytes via the signal transducer and activator of transcription (STAT) 3 pathway. After activation of Gp130 with leukemia inhibitory factor (LIF), expression of VEGF mRNA rapidly increased with a peak at 3 h in cultured cardiac myocytes. Cardiotrophin-1 also enhanced VEGF mRNA expression in a dose-dependent manner. VEGF protein production and secretion to the medium were also enhanced by LIF and cardiotrophin-1 but not by interleukin-6. Adenovirus transfer of the dominant-negative form of STAT3 to cultured cardiac myocytes inhibited induction of VEGF expression induced by LIF, but neither PD98059 nor wortmannin was affected. In murine hearts, intravenous administration of LIF augmented expression of VEGF mRNA; however, the hearts of transgenic mice overexpressing dominant-negative STAT3 showed reduced expression of VEGF mRNA that was not induced after LIF stimulation. These data provide the first evidence that a STAT family protein functions as a regulator of angiogenic growth factors and suggest that Gp130/STAT signaling in cardiac myocytes can control vessel growth during cardiac remodeling.
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ACTIVATION OF PHOSPHATIDYLINOSITOL 3-KINASE THROUGH Glycoprotein 130 INDUCES PROTEIN KINASE B AND P70 S6 KINASE PHOSPHORYLATION IN CARDIAC MYOCYTES
The Journal of biological chemistry, 1998Co-Authors: Yasushi Fujio, Tadamitsu Kishimoto, Keita Kunisada, Hisao Hirota, Hideo Matsui, Keiko Yamauchi-takiharaAbstract:Phosphatidylinositol (PI) 3-kinase is known to be activated by cytokine stimulation through different types of receptors to transduce intracellular responses. We have previously reported that leukemia inhibitory factor (LIF) induces the activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein (MAP) kinase pathways through Glycoprotein (Gp) 130 in cardiac myocytes. However, whether PI 3-kinase is involved in regulation of Gp130 signaling and the activation mechanisms by which it associates with other tyrosine-phosphorylated proteins remain unknown. We found that LIF induced the activation of PI 3-kinase in cardiac myocytes. Moreover, JAK1 binds to PI 3-kinase, and LIF stimulation increases the PI 3-kinase activity in JAK1 immunoprecipitates. Activation of MAP kinase and protein kinase B by LIF was attenuated by wortmannin. LIF-induced p70 S6 kinase activation, protein synthesis, and c-fos mRNA expression were inhibited by wortmannin and rapamycin. Both inhibitors failed to appreciably affect the phosphorylation of STAT3. In conclusion, PI 3-kinase is activated with LIF in cardiac myocytes, and JAK1 is found to associate with this enzyme. PI 3-kinase provides a crucial link between Gp130, MAP kinase, protein kinase B, and p70 S6 kinase in cardiac myocytes.
Hidenobu Tanihara - One of the best experts on this subject based on the ideXlab platform.
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Preferential differentiation of neural progenitor cells into the glial lineage through Gp130 signaling in N-methyl-D-aspartate-treated retinas.
Brain research, 2005Co-Authors: Yuki Mawatari, Tetsuya Taga, Mikiko Fukushima, Toshihiro Inoue, Takao Setoguchi, Hidenobu TaniharaAbstract:The purpose of this study was to investigate the differentiation of neural progenitor cells (NPCs) following retinal transplantation in N-methyl-D-aspartate (NMDA)-treated eyes. NMDA was injected into the vitreous cavity of adult rat eyes. NPCs were prepared from telencephalic neuroepithelium of enhanced green fluorescence protein (EGFP) transgenic mice on embryonic day 14.5. A cell suspension was injected into the vitreous cavity in experimental eyes. Immunohistochemistry was conducted at 1, 2 or 4 weeks after transplantation of NPCs in an effort to determine the survival and differentiation of transplanted NPCs. Similar experiments were conducted using Glycoprotein (Gp)130-null (-/-) mice. Examination of retinal sections revealed that transplanted NPCs could survive for at least 4 weeks in NMDA-treated retinas. Immunohistochemical studies for specific cell-type markers revealed that, among the transplanted NPCs at 2 weeks after transplantation, the mean percentage (+/-standard deviation) of glial fibrillary acidic protein (GFAP)-positive (glial) cells was 63.5 +/- 7.4%, demonstrating the differentiation of transplanted NPCs with a preference for the glial lineage. Furthermore, the mean percentage of betaIII-tubulin-positive (mature neuronal) cells was 18.8 +/- 4.5%. Following transplantation of NPCs isolated from Gp130-/- mice into NMDA-treated retinas, the mean percentage of GFAP-positive cells (17.6 +/- 7.0%), was significantly lower than that in NPCs isolated from wild-type mice (59.1 +/- 6.0%, P = 0.04, Mann-Whitney U test). Preferential differentiation of NPCs into the glial lineage is induced through Gp130 signaling in NMDA-treated eyes.
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Preferential differentiation of neural progenitor cells into the glial lineage through Gp130 signaling in N-methyl-D-aspartate-treated retinas.
Brain Research, 2005Co-Authors: Yuki Mawatari, Tetsuya Taga, Mikiko Fukushima, Toshihiro Inoue, Takao Setoguchi, Hidenobu TaniharaAbstract:Abstract The purpose of this study was to investigate the differentiation of neural progenitor cells (NPCs) following retinal transplantation in N -methyl- d -aspartate (NMDA)-treated eyes. NMDA was injected into the vitreous cavity of adult rat eyes. NPCs were prepared from telencephalic neuroepithelium of enhanced green fluorescence protein (EGFP) transgenic mice on embryonic day 14.5. A cell suspension was injected into the vitreous cavity in experimental eyes. Immunohistochemistry was conducted at 1, 2 or 4 weeks after transplantation of NPCs in an effort to determine the survival and differentiation of transplanted NPCs. Similar experiments were conducted using Glycoprotein (Gp)130-null (−/−) mice. Examination of retinal sections revealed that transplanted NPCs could survive for at least 4 weeks in NMDA-treated retinas. Immunohistochemical studies for specific cell-type markers revealed that, among the transplanted NPCs at 2 weeks after transplantation, the mean percentage (±standard deviation) of glial fibrillary acidic protein (GFAP)-positive (glial) cells was 63.5 ± 7.4%, demonstrating the differentiation of transplanted NPCs with a preference for the glial lineage. Furthermore, the mean percentage of βIII-tubulin-positive (mature neuronal) cells was 18.8 ± 4.5%. Following transplantation of NPCs isolated from Gp130−/− mice into NMDA-treated retinas, the mean percentage of GFAP-positive cells (17.6 ± 7.0%), was significantly lower than that in NPCs isolated from wild-type mice (59.1 ± 6.0%, P = 0.04, Mann–Whitney U test). Preferential differentiation of NPCs into the glial lineage is induced through Gp130 signaling in NMDA-treated eyes.