DOI： 10.1016/j.neures.2009.09.374

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Language：English   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.mod.2009.06.730

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

It has been suggested that Oct-3/4 may regulate self-renewal in somatic stem cells, as it does in embryonic stem cells. However, recent reports raise the possibility that detection of human Oct-3/4 expression by RT-PCR is prone to artifacts generated by pseudogene transcripts and argue against a role for Oct-3/4 in somatic cells. In this study, we clarified Oct-3/4 expression in mouse somatic tissues using designed PCR primers, which can exclude amplification of its pseudogenes. We found that novel alternative transcripts are indeed expressed in somatic tissues, rather than the normal length transcripts in germline and ES cells. The alternative transcripts indicate the expression of two kinds of truncated proteins. Furthermore, we determined novel promoter regions that are sufficient for the expression of Oct-3/4 transcript variants in somatic cells. These findings provide new insights into the postnatal role of Oct-3/4 in somatic tissues.

DOI： 10.1074/jbc.M802992200

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The regeneration of lens tissue from the iris of newts has become a classical model of developmental plasticity, although little is known about the corresponding plasticity of the mammalian iris. We here demonstrate and characterize multipotent cells within the iris pigment epithelium (IPE) of postnatal and adult rodents. Acutely-isolated IPE cells were morphologically homogeneous and highly pigmented, but some produced neurospheres which expressed markers characteristic of neural stem/progenitor cells. Stem/progenitor cell markers were also expressed in the IPE in vivo both neonatally and into adulthood. Inner and outer WE layers differentially expressed Nestin (Nes) in a manner suggesting that they respectively shared origins with neural retina (NR) and pigmented epithelial (RPE) layers. Transgenic marking enabled the enrichment of Nes-expressing IPE cells ex vivo, revealing a pronounced capacity to form neurospheres and differentiate into photoreceptor cells. IPE cells that did not express Nes were less able to form neurospheres, but a subset initiated the expression of pan-neural markers in primary adherent culture. These data collectively suggest that discrete populations of highly-pigmented cells with heterogeneous developmental potencies exist postnatally within the IPE, and that some of them are able to differentiate into multiple neuronal cell types. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ydbio.2006.12.047

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Language：English   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

DOI： 10.1016/j.ydbio.2007.03.574

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DOI： 10.1016/j.neures.2007.06.328

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIO SCIENTIFICA LTD  

The success rate is generally higher when cloning mice from embryonic stem (ES) cell nuclei than from somatic cell nuclei, suggesting that the embryonic nature or the undifferentiated state of the donor cell increases cloning efficiency. We assessed the developmental ability of cloned embryos derived from cultured neural stem cell (NSC) nuclei and compared the success rate with that of embryos cloned from other donor cells such as differentiated NSCs, cumulus cells, Sertoli cells and ES cells in the mouse. The transfer of two-cell cloned embryos derived from cultured NSC nuclei into surrogate mothers produced five live cloned mice. However, the success rate (0.5%) was higher in embryos cloned from cultured NSC nuclei than from differentiated NSCs (0%), but lower than that obtained by cloning mice from other cell nuclei (2.2-3.50%). Although the in vitro developmental potential to the two-cell stage of the cloned embryos derived from NSC nuclei (73%) was similar to that of the cloned embryos derived from other somatic cell nuclei (e.g., 85% in Sertoli cells and 75% in cumulus cells), the developmental rate to the morula-blastocyst stage was only 7%. This rate is remarkably lower than that produced from other somatic cells (e.g., 50% in Sertoli cells and 54% in cumulus cells). These results indicate that the undifferentiated state of neural cells does not enhance the cloning efficiency in mice and that the arrest point for in vitro development of cloned embryos depends on the donor cell type.

DOI： 10.1530/rep.1.01010

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Neural stem cells/progenitors that give rise to neurons and glia have been identified in different regions of the brain.. including the embryonic retina and ciliary epithelium of the adult eye. Here, we first demonstrate the characterization of neural stem/progenitors in postnatal iris pigment epithelial (IPE) cells. Pure isolated IPE cells could form spheres that contained cells expressing retinal progenitor markers in non-adherent culture. The spheres grew by cell proliferation, as indicated by bromodeoxyuridine incorporation. When attached to laminin, the spheres forming IPE derived cells were able to exhibit neural phenotypes, including retinal-specific neurons. When co-cultured with embryonic retinal cells, or grafted into embryonic retina in vivo, the IPE cells could also display the phenotypes of photoreceptor neurons and Muller glia. Our results suggest that the IPE derived cells have retinal stem/progenitor properties and neurogenic potential without gene transfer, thereby providing a novel potential source for both basic stem cell biology and therapeutic applications for retinal diseases. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ydbio.2005.10.035

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

We investigated the ability of adult human RPE cells to differentiate into neurons. Two cell lines were evaluated. The cells were cultured in medium with 8% serum, transferred to a neural stem cell maintenance culture, and induced to differentiate with retinoic acid. The cells were immunocytochemically examined at each step. The cells showed epithelial-like morphology with 8% serum and all were immunoreactive for beta-III tubulin. After transfer to the stem cell maintenance culture, they changed morphologically and became immunoreactive for MAP5 and neurofilament200 after inducement with retinoic acid. The ratio of MAP5 positive cells was higher in the young adult RPE cell line. No GFAP or rod-opsin immunoreactive cells were observed. Adult human RPE cells even from old person are capable of differentiating into neurons, although the ratio of mature neurons was greater in the young than in the old cell line in this condition. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.01.172

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE AMERICA INC  

DOI： 10.1038/nn762

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

RETINAL ganglion cells (RGCs) survive axotomy and regenerate their axons into the peripheral nerve graft in adult mammals. To understand the potential role of fibroblast growth factors (FGFs) in survival and regeneration of axotomized RGCs, we examined FGF receptor 1 (FGFR-1) localization in normal and PN grafted ferret retinas by immunohistochemistry in combination with retrograde labeling. Prominent expression of FGFR-1 was observed in outer plexiform layer and ganglion cell layer of normal ferret retina. In the ganglion cell layer, FGFR-1 immunoreactivity was detected in about 30% of RGCs, predominantly in large cells. In the PN grafted ferret retina, 90% of RGCs with regenerated axons expressed FGFR-1. Our findings suggest that FGFs may play an important role in the survival and axonal regeneration of RGCs of adult mammals. (C) 1999 Lippincott Williams & Wilkins.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

Dissociated cells of the iris-pigmented epithelium (IPE) from a 1-day-old chick grew in monolayer culture and stably maintained their differentiated state when cultured with standard culture medium. After replacement of the control medium by EdFPH medium, which is effective in inducing dedifferentiation of retinal pigmented epithelium (RPE) cells, all cells rapidly lost pigment granules, proliferated intensively, and dedifferentiated. By further addition of ascorbic acid, dedifferentiated cells accumulated and formed a large number of lentoids, This system provides a useful opportunity for analyzing cellular and molecular mechanism involved in each step of transdifferentiation. Furthermore, Northern blot data indicates that the up-regulation of pax-6 gene could be an important event during lens regeneration as well as during normal lens development, (C) 1998 Academic Press.

DOI： 10.1006/excr.1998.4211

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI PUBL IRELAND LTD  

cis-Diammine dichloroplatinum(II) (CDDP) is the salt of a platinum compound which has been noted to have a wide spectrum of activity against malignant disorders. We have studied the effects of CDDP on embryonal carcinoma F9 cell differentiation. In the presence of this agent in vitro, the cells showed rapid morphological changes, a marked increase in the mRNA expression of various differentiation markers accompanied by a loss of tumorigenicity. These results indicate that the differentiation of F9 cells is induced with CDDP.

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Changes in Hox1.6 and c-jun gene expression were examined upon F9 cell differentiation that was induced by three independent methods: a drug treatment with retinoic acid (RA), that with sodium butyrate (NaB), and a genetic approach using the ts mutant. To obtain further information on the mechanism of teratocarcinoma cell differentiation we have examined the kinetics of the induction of Hox1.6 and c-jun mRNA whose gene products have been demonstrated to have specific roles in gene regulation. Expression of Hox1.6 mRNA was induced more rapidly than c-jun mRNA by all the above three inducing methods. Furthermore, protein synthesis was not required for the induction of Hox1.6 mRNA as well as of c-jun mRNA synthesis in all three methods. The data suggested that the transcriptional increase in the Hox1.6 mRNA was a primary response and could play an important role in F9 cell differentiation. © 1995, Society for In Vitro Biology. All rights reserved.

DOI： 10.1007/BF02634259

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

Both retinoic acid (RA) and sodium butyrate (NaB) induce differentiation in embryonal carcinoma F9 cells. Phenotypic changes caused by RA are irreversible, whereas those of NaB are rapid and reversible. In this study, we investigated the effects of combinations of these two agents on F9 cell differentiation and showed that RA had no effect on the cells induced to differentiate with NaB and vice versa. Thus, F9 cells are induced to differentiate along two distinct pathways which are mutually exclusive.

DOI： 10.1111/j.1440-169X.1994.00223.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1006/excr.1993.1271

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Language：English   Publishing type：Research paper (scientific journal)  

The temperature‐sensitive (ts) mutants of cell differentiation derived from the mouse teratocarcinoma cell line F9, when exposed to non‐permissive temperature, undergo stem‐cell differentiation concomitant with a transient retardation of cell‐cycle progression. By incubating these mutant strains at non‐permissive temperature, we were able to study the relationship between cell differentiation and tumorigenicity. Upon exposure to non‐permissive temperature, the mutant cells undergo extensive differentiation and lose their ability to initiate tumors in vivo, but retain their in vitro proliferative potential. Our data suggest that the loss of tumorigenicity is not caused by altered proliferative potential, but rather by cell differentiation. We therefore suggest that the loss of proliferative potential and the onset of cell differentiation in teratocarcinoma F9 cells are 2 independent events which can be genetically dissected, and that there is (a) crucial step(s) in the differentiation pathway at which these ts mutant cells lose their tumorigenicity. Copyright © 1993 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ijc.2910540228

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Language：English   Publishing type：Research paper (scientific journal)  

To obtain information on the mechanism of teratocarcinoma cell differentiation, the expression of genes having a specific role in gene regulation was examined using three different methods of inducing differentiation: Drug treatments with retinoic acid (RA) and sodium butyrate, and a genetic approach using ts mutants. The RAR-β and MK genes were induced specifically by RA treatment, which indicates that these two genes are solely RA responsive. By contrast, a change in c-jun, Hox 1.6, and Oct-3 gene expression was observed in all three methods of F9 cell differentiation. These findings suggest that these three genes, whether down-or up-regulated, play an important and key role during teratocarcinoma cell differentiation. © 1993 Academic Press, Inc.

DOI： 10.1006/excr.1993.1055

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：STOCKTON PRESS  

We have previously reported the isolation of several temperature-sensitive (ts) mutants of F9 cells. Further investigations showed that some mutants were induced to differentiate at non-permissive temperature of cell growth, accompanied by changes in the expression of various genes, whereas others were not. During the differentiation induced by shifting up to the nonpermissive temperature, a rapid and transient decrease in both c-myc and p53 mRNA levels and rapid induction of c-jun mRNA were observed. These changes were specific in differentiation-inducible mutants and were not observed in a non-inducible mutant. In both types of mutants, the level of c-myc mRNA decreased in association with growth retardation at the non-permissive temperature. The p53 mRNA, however, showed specific increase in the differentiation-inducible ts mutants. These observations suggest distinct roles for p53 and c-myc from proliferation to differentiation in teratocarcinoma stem cells.

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/0014-4827(92)90390-t

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Sodium butyrate (NaB) can induce teratocarcinoma cell differentiation as retinoic acid (RA). However, the function of these two agents seems to be a little different [Kosaka et al., Exp Cell Res, 192:46-51, 1991]. F9 cells treated with NaB synthesize both tissue-type (tPA) and urokinase-type (uPA) plasminogen activator, though RA induces only tPA production. Urokinase-type PA is demonstrated to exist in association with membrane and to localize its activity to the close environment of the cell surface. This may cause the specific cell morphology and characteristics of differentiated F9 cells induced with NaB.

DOI： 10.1002/jcb.240490311

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/0014-4827(91)90155-n

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DOI： 10.1016/0006-291x(89)91034-6

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Nucleoside analogues inhibiting DNA synthesis can induce cell differentiation in teratocarcinoma cells. We have examined how their abilities to induce F9 cell differentiation were specifically counterbalanced by their corresponding normal nucleosides. We have also compared the differentiation inducing ability of the wild type F9 cells with that of its thymidine kinase-less mutant using plasminogen activator, as a differentiation marker, which is expressed at a very early stage of endodermal cell differentiation and can be assayed quantitatively. The results obtained were clearly explainable by the conventionally accepted action mechanisms of the nucleoside analogues, thus strongly suggesting that their abilities to induce cell differentiation were direct consequences of the inhibition of DNA synthesis
thus this confirms the notion that a close association exists between the inhibition of DNA synthesis and the induction of teratocarcinoma stem cell differentiation. © 1989.

DOI： 10.1016/0006-291X(89)91118-2

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本解剖学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本臓器保存生物医学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本臓器保存生物医学会  

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Authorship：Corresponding author   Language：English   Publisher：日本発生生物学会・日本細胞生物学会  

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Authorship：Corresponding author   Language：English   Publisher：日本発生生物学会・日本細胞生物学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：Japanese   Publisher：日本結合組織学会・マトリックス研究会  

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Language：English   Publisher：日本発生生物学会・日本細胞生物学会  

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Event date： 2020.3.27 - 2020.3.29

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：新潟  

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Event date： 2018.10.20 - 2018.10.21

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Event date： 2017.10.28 - 2017.10.29

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Venue：長崎大学  

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Event date： 2015.1.26

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Venue：広島  

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Event date： 2014.9.4

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Event date： 2013.10.19 - 2013.10.20

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Applicant：独立行政法人科学技術振興機構

Application no：JP2004008222  Date applied：2004.6.11

Announcement no：WO2004-111213  Date announced：2004.12.23

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Application no：JP2004008120  Date applied：2004.6.10

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Application no：特願2002-136321  Date applied：2002.5.10

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Applicant：独立行政法人科学技術振興機構

Application no：特願2002-136321  Date applied：2002.5.10

Announcement no：特開2003-325167  Date announced：2003.11.18

Patent/Registration no：特許第3723152号  Date issued：2005.9.22

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