Updated on 2021/12/26

写真a

 
KOSAKA Mitsuko
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Assistant Professor
Position
Assistant Professor
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Degree

  • 医学 ( 大阪大学 )

Research Interests

  • iris epithelium

  • stem cell

  • development and regeneration

  • cancer

  • cell differentiation

Research Areas

  • Life Science / Developmental biology

  • Life Science / Tumor biology

  • Life Science / Anatomy

Education

  • 大阪大学大学院医学研究科博士課程    

    1988.4 - 1992.3

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  • 大阪大学大学院医学研究科修士過程    

    1986.4 - 1988.3

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  • Osaka University   薬学部   薬学科

    1982.4 - 1986.3

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Research History

  • Okayama University   医歯薬学総合研究科   Assistant Professor

    2010.4

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  • 岡山県産業活性化事業

    2009.9 - 2012.3

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  • 理化学研究所発生再生科学総合研究センター   ユニットリーダー

    2003.10 - 2008.3

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  • 科学技術振興事業団   さきがけ21研究者

    2000.10 - 2003.9

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  • Kyoto University   Institute for Frontier Medical Sciences

    2000.4 - 2005.3

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  • 倉敷成人病センター   主任研究員

    1999.4 - 2000.3

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  • 科学技術振興財団   さきがけ21研究者

    1996.10 - 1999.9

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  • National Institute for Basic Biology   形態形成部門   Research Assistant

    1994.4 - 1997.3

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  • Osaka University   Research Institute for Microbial Diseases

    1992.4 - 1994.3

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Professional Memberships

  • 日本がん転移学会

    2021.1

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  • THE JAPANESE ASSOCIATION OF ANATOMISTS

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  • JAPANESE SOCIETY OF DEVELOPMENTAL BIOLOGISTS

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Papers

  • Prognostic value of OCT4A and SPP1C transcript variant co-expression in early-stage lung adenocarcinoma. Reviewed International journal

    Seijiro Koshimune, Mitsuko Kosaka, Nobuhiko Mizuno, Hiromasa Yamamoto, Tomoyuki Miyamoto, Kohta Ebisui, Shinichi Toyooka, Aiji Ohtsuka

    BMC cancer   20 ( 1 )   521 - 521   2020.6

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    BACKGROUND: Octamer-binding transcription factor 4A (OCT4A) is essential for cell pluripotency and reprogramming both in humans and mice. To date, however, the function of human OCT4 in somatic and/or tumour tissues is largely unknown. METHODS: RT-PCR was used to identify full-length splice forms of OCT4 transcripts in normal and cancer cells. A FLAG-tagged OCT4 genomic transgene was used to identify OCT4-positive cancer cells. A potential role for OCT4 in somatic cancer cells was examined by cell ablation of OCT4-positive cells using promoter-driven diphtheria toxin A. OCT4 and secreted phosphoprotein 1 (SPP1) transcripts in early-stage lung adenocarcinoma tumours were analysed and compared with pathohistological features. RESULTS: The results show that, unlike in murine cells, OCT4A and OCT4B variants are transcribed in both human cancer cells and in adult tissues such as lung, kidney, uterus, breast, and eye. We found that OCT4A and SPP1C are co-expressed in highly aggressive human breast, endometrial, and lung adenocarcinoma cell lines, but not in mesothelial tumour cell lines. Ablation of OCT4-positive cells in lung adenocarcinoma cells significantly decreased cell migration and SPP1C mRNA levels. The OCT4A/SPP1C axis was found in primary, early-stage, lung adenocarcinoma tumours. CONCLUSIONS: Co-expression of OCT4 and SPP1 may correlate with cancer aggressiveness, and the OCT4A/SPP1C axis may help identify early-stage high-risk patients with lung adenocarcinoma. Contrary to the case in mice, our data strongly suggest a critical role for OCT4A and SPP1C in the development and progression of human epithelial cancers.

    DOI: 10.1186/s12885-020-06969-0

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  • Conclusive Evidence for OCT4 Transcription in Human Cancer Cell Lines: Possible Role of a Small OCT4-Positive Cancer Cell Population Reviewed

    STEM CELLS   36 ( 9 )   1341 - 1354   2018.5

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/stem.2851

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  • Immediate differentiation of neuronal cells from stem/progenitor-like cells in the avian iris tissues Reviewed

    Tamami Matsushita, Ai Fujihara, Lars Royall, Satoshi Kagiwada, Mitsuko Kosaka, Masasuke Araki

    EXPERIMENTAL EYE RESEARCH   123   16 - 26   2014.6

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

    A simple culture method that was recently developed in our laboratory was applied to the chick iris tissues to characterize neural stem/progenitor-like cells. Iris tissue is a non-neuronal tissue and does not contain any neuronal cells. In the present study we isolated iris tissues from chick embryos just prior to hatching. The isolated iris pigmented epithelium (IPE) or the stroma was embedded in Matrigel and cultured in Dulbecco's MEM supplemented with either fetal bovine serum or the synthetic serum replacement solution B27. Within 24 h of culture, elongated cells with long processes extended out from the explants of both tissues and were positively stained for various neuronal markers such as transitin, Tuj-1 and acetylated tubulin. After a longer culture period, cells positive for photoreceptor markers like rhodopsin, iodopsin and visinin were found, suggesting that the iris tissues contain retinal stem/progenitor-like cells. Several growth factors were examined to determine their effects on neuronal differentiation. EGF was shown to dramatically enhance neuronal cell differentiation, particularly the elongation of neuronal fibers. The addition of exogenous FGF2, however, did not show any positive effects on neuronal differentiation, although FGF signaling inhibitor, SU5402, suppressed neuronal differentiation. The results show that neuronal stem/progenitor-like cells can differentiate into neuronal cells immediately after they are transferred into an appropriate environment. This process did not require any exogenous factors, suggesting that neural stem/progenitor-like cells are simply suppressed from neuronal differentiation within the tissue, and isolation from the tissue releases the cells from the suppression mechanism. (C) 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.exer.2014.04.007

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  • Architecture of the subendothelial elastic fibers of small blood vessels and variations in vascular type and size Reviewed

    Akira Shinaoka, Ryusuke Momota, Eri Shiratsuchi, Mitsuko Kosaka, Kanae Kumagishi, Ryuichi Nakahara, Ichiro Naito, Aiji Ohtsuka

    Microscopy and Microanalysis   19 ( 2 )   406 - 414   2013.4

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    Most blood vessels contain elastin that provides the vessels with the resilience and flexibility necessary to control hemodynamics. Pathophysiological hemodynamic changes affect the remodeling of elastic components, but little is known about their structural properties. The present study was designed to elucidate, in detail, the three-dimensional (3D) architecture of delicate elastic fibers in small vessels, and to reveal their architectural pattern in a rat model. The fine vascular elastic components were observed by a newly developed scanning electron microscopy technique using a formic acid digestion with vascular casts. This method successfully visualized the 3D architecture of elastic fibers in small blood vessels, even arterioles and venules. The subendothelial elastic fibers in such small vessels assemble into a sheet of meshwork running longitudinally, while larger vessels have a higher density of mesh and thicker mesh fibers. The quantitative analysis revealed that arterioles had a wider range of mesh density than venules
    the ratio of density to vessel size was higher than that in venules. The new method was useful for evaluating the subendothelial elastic fibers of small vessels and for demonstrating differences in the architecture of different types of vessels. © Microscopy Society of America 2013.

    DOI: 10.1017/S1431927612014341

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  • Tsukushi functions as a Wnt signaling inhibitor by competing with Wnt2b for binding to transmembrane protein Frizzled4 Reviewed

    Kunimasa Ohta, Ayako Ito, Sei Kuriyama, Giuseppe Lupo, Mitsuko Kosaka, Shin-ichi Ohnuma, Shinichi Nakagawa, Hideaki Tanaka

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   108 ( 36 )   14962 - 14967   2011.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATL ACAD SCIENCES  

    The Wnt signaling pathway is essential for the development of diverse tissues during embryogenesis. Signal transduction is activated by the binding of Wnt proteins to the type I receptor low-density lipoprotein receptor-related protein 5/6 and the seven-pass transmembrane protein Frizzled (Fzd), which contains a Wnt-binding site in the form of a cysteine-rich domain. Known extracellular antagonists of the Wnt signaling pathway can be subdivided into two broad classes depending on whether they bind primarily to Wnt or to low-density lipoprotein receptor-related protein 5/6. We show that the secreted protein Tsukushi (TSK) functions as a Wnt signaling inhibitor by binding directly to the cysteine-rich domain of Fzd4 with an affinity of 2.3 x 10(-10) M and competing with Wnt2b. In the developing chick eye, TSK is expressed in the ciliary/iris epithelium, whereas Wnt2b is expressed in the adjacent anterior rim of the optic vesicle, where it controls the differentiation of peripheral eye structures, such as the ciliary body and iris. TSK overexpression effectively antagonizes Wnt2b signaling in chicken embryonic retinal cells both in vivo and in vitro and represses Wnt-dependent specification of peripheral eye fates. Conversely, targeted inactivation of the TSK gene in mice causes expansion of the ciliary body and up-regulation of Wnt2b and Fzd4 expression in the developing peripheral eye. Thus, we uncover a crucial role for TSK as a Wnt signaling inhibitor that regulates peripheral eye formation.

    DOI: 10.1073/pnas.1100513108

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  • Molecular function of Tsukushi on neuronal stem cells Reviewed

    Ohta Kunimasa, Ito Ayako, Kuriyama Sei, Lupo Giuseppe, Nakayama Rika, Ohshima Naoko, Kosaka Mitsuko, Ohnuma Shin-ichi, Nakagawa Shinichi, Tanaka Hideaki

    Neuroscience Research   65   S91   2009

  • Tsukushi is a Frizzled ligand that, in competition with Wnt2b, regulates the proliferation of retinal stem/progenitor cells Reviewed

    Ohta Kunimasa, Ito Ayako, Kuriyama Sei, Lupo Giuseppe, Nakayama Rika, Ohshima Naoko, Kosaka Mitsuko, Ohnuma Shin-ichi, Nakagawa Shinichi, Tanaka Hideaki

    Mechanisms of Development   126   S273   2009

  • Novel Variants of Oct-3/4 Gene Expressed in Mouse Somatic Cells Reviewed

    Nobuhiko Mizuno, Mitsuko Kosaka

    JOURNAL OF BIOLOGICAL CHEMISTRY   283 ( 45 )   30997 - 31004   2008.11

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    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.

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  • Tsukushi is a Frizzled4 ligand that regulates the proliferation of retinal stem cells in competition with Wnt2b Reviewed

    Ohta Kunimasa, Ito Ayako, Kuriyama Sei, Nakayama Rika, Oshima Naoko, Kosaka Mitsuko, Ohnuma Shinichi, Nakagawa Shinichi, Tanaka Hideaki

    Neuroscience Research   61   S42   2008

  • Multipotent cells from mammalian iris pigment epithelium Reviewed

    Maki Asami, Guangwei Sun, Masahiro Yamaguchi, Mitsuko Kosaka

    DEVELOPMENTAL BIOLOGY   304 ( 1 )   433 - 446   2007.4

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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.

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  • Tsukushi inhibits the proliferation of retinal stem/progenitor cells Reviewed

    Ohta Kunimasa, Ito Ayako, Kuriyama Sei, Ohnuma Shinichi, Kosaka Mitsuko, Nakagawa Shinichi, Tanaka H

    Developmental Biology   306 ( 1 )   391   2007

  • Tsukushi inhibits proliferation of retinal stem cells by Wnt signalling inhibition Reviewed

    Ohta Kunimasa, Ito Ayako, Kuriyama Sei, Ohnuma Shin-Ichi, Kosaka Mitsuko, Nakagawa Shin-Ichi, Tanaka Hideaki

    Neuroscience Research   58   S56   2007

  • Developmental ability of cloned embryos from neural stem cells Reviewed

    Eiji Mizutani, Hiroshi Ohta, Satoshi Kishigami, Nguyen Van Thuan, Takafusa Hikichi, Sayaka Wakayama, Mitsuko Kosaka, Eimei Sato, Teruhiko Wakayama

    REPRODUCTION   132 ( 6 )   849 - 857   2006.12

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    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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  • Retinal stem/progenitor properties of iris pigment epithelial cells Reviewed

    GW Sun, M Asami, H Ohta, J Kosaka, M Kosaka

    DEVELOPMENTAL BIOLOGY   289 ( 1 )   243 - 252   2006.1

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    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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  • Adult human retinal pigment epithelial cells capable of differentiating into neurons Reviewed

    K Amemiya, M Haruta, M Takahashi, M Kosaka, G Eguchi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   316 ( 1 )   1 - 5   2004.3

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    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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  • Induction of photoreceptor-specific phenotypes in adult mammalian iris tissue Reviewed

    M Haruta, M Kosaka, Y Kanegae, Saito, I, T Inoue, R Kageyama, A Nishida, Y Honda, M Takahashi

    NATURE NEUROSCIENCE   4 ( 12 )   1163 - 1164   2001.12

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    DOI: 10.1038/nn762

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  • Localization of FGFR-1 in axotomized and peripheral nerve transplanted ferret retina Reviewed

    MZ Quan, M Kosaka, M Watanabe, Y Fukuda

    NEUROREPORT   10 ( 18 )   3903 - 3907   1999.12

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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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  • In vitro culture system for iris-pigmented epithelial cells for molecular analysis of transdifferentiation Reviewed

    M Kosaka, R Kodama, G Eguchi

    EXPERIMENTAL CELL RESEARCH   245 ( 2 )   245 - 251   1998.12

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    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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  • INDUCTION OF TERATOCARCINOMA F9 CELL-DIFFERENTIATION WITH CIS-DIAMMINE DICHLOROPLATINUM(II) (CDDP) Reviewed

    T DOI, T SUMI, Y NISHINA, M KOSAKA, SA IWAI, M SAKUDA, Y NISHIMUNE

    CANCER LETTERS   88 ( 1 )   81 - 86   1995.1

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    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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  • The kinetics of induction of Hox1.6 and c-jun mRNA during three different ways of inducing differentiation in teratocarcinoma F9 cells Reviewed

    Souichi A. Iwai, Yukio Nishina, Mitsuko Kosaka, Tetsuro Sumi, Toshihide Doi, Masayoshi Sakuda, Yoshitake Nishimune

    In Vitro Cellular & Developmental Biology - Animal: Journal of the Society for In Vitro Biology   31 ( 6 )   462 - 466   1995

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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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  • F9 cells can be differentiated toward 2 distinct, mutually exclusive pathways by Reitnoic acid and Sodium butyrate. Reviewed

    M KOSAKA, M TAKEDA, K MATSUMOTO, Y NISHIMUNE

    DEVELOPMENT GROWTH & DIFFERENTIATION   36 ( 2 )   223 - 230   1994.4

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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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  • The Induction of jun Genes during the Reversible Changes Induced with Sodium Butyrate on the Differentiation of F9 Cells Reviewed

    Yukio Nishina, Tetsuro Sumi, Souichi A. Iwai, Mitsuko Kosaka, Yoshitake Nishimune

    Experimental Cell Research   208 ( 2 )   492 - 497   1993.10

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    DOI: 10.1006/excr.1993.1271

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  • Suppression of tumorigenicity in temperature‐sensitive mutants of embryonal carcinoma cells by induction of cell differentiation at non‐permissive temperature Reviewed

    Tetsuro Sumi, Masayoshi Sakuda, Yukio Nishina, Mitsuko Kosaka, Yoshitakc Nishimune

    International Journal of Cancer   54 ( 2 )   333 - 337   1993

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    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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  • Changes in Hox1.6, c-jun, and Oct-3 gene expressions are associated with teratocarcinoma F9 cell differentiation in three different ways of induction Reviewed

    Souichi A. Iwai, Mitsuko Kosaka, Yukio Nishina, Tetsuro Sumi, Masayoshi Sakuda, Yoshitake Nishimune

    Experimental Cell Research   205 ( 1 )   39 - 43   1993

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    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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  • C-MYC AND P53 GENE-EXPRESSION IN THE DIFFERENTIATION OF TEMPERATURE-SENSITIVE MUTANTS OF TERATOCARCINOMA F9 CELLS Reviewed

    M KOSAKA, SA IWAI, Y NISHINA, T SUMI, Y NISHIMUNE

    ONCOGENE   7 ( 12 )   2455 - 2460   1992.12

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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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  • Expression of c-kit protooncogene is stimulated by cAMP in differentiated F9 mouse teratocarcinoma cells Reviewed

    Yukio Nishina, Yuhki Kobarai, Tetsuro Sumi, Mitsuko Kosaka, Shin-ichi Nishikawa, Yoshitake Nishimune

    Experimental Cell Research   198 ( 2 )   352 - 356   1992.2

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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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  • Teratocarcinoma F9 cells induced to differentiate with sodium butyrate produce both tissue‐type and urokinase‐type plasminogen activators Reviewed

    Masashi Takeda, Mitsuko Kosaka, Yukio Nishina, Ken Sawada, Keishi Matsumoto, Yoshitake Nishimune

    Journal of Cellular Biochemistry   49 ( 3 )   284 - 289   1992

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    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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  • Reversible effects of sodium butyrate on the differentiation of F9 embryonal carcinoma cells Reviewed

    Mitsuko Kosaka, Yukio Nishina, Masashi Takeda, Keishi Matsumoto, Yoshitake Nishimune

    Experimental Cell Research   192 ( 1 )   46 - 51   1991.1

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    DOI: 10.1016/0014-4827(91)90155-n

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  • Isolation of mutants showing temperature-sensitive cell growth from embryonal carcinoma cells: Control of stem cell differentiation by incubation temperatures Reviewed

    Yoshitake Nishimune, Yukio Nishina, Tetsuro Sumi, Mitsuko Kosaka, Masashi Takeda, Keishi Matsumoto, Aizo Matsushiro, Masayoshi Sakuda

    Biochemical and Biophysical Research Communications   165 ( 1 )   65 - 72   1989.11

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    DOI: 10.1016/0006-291x(89)91034-6

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  • Inhibition of DNA synthesis causes stem cell differentiation: Induction of teratocarcinoma F9 cell differentiation with nucleoside analogues of DNA-synthesis inhibitors and their inducing abilities counterbalanced specifically by normal nucleosides Reviewed

    Yoshitake Hishimune, Mitsuko Kosaka, Yukio Nishina, Tetsuro Sumi, Masayoshi Sakuda, Masashi Takeda, Keishi Matsumoto

    Biochemical and Biophysical Research Communications   163 ( 3 )   1290 - 1297   1989.9

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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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Books

  • Iris pigment epithelium as a potential source for both basic biology and therapeutic applications for retinal regeneration. Strategies for retinal tissue repair and regeneration in vertebrates: from fish to human

    Kosaka Mitsuko( Role: Sole author)

    Research Signpost  2007 

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  • Multipotentiality of iris pigment epithelial cells in vertebrate eye.

    Mitsuko Kosaka, Guangwei Sun, M Haruta, M Takahashi( Role: Sole author)

    Humana Press, Canada  2004.10 

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MISC

  • Clinical value of OCT4A/SPP1C axis in endometrial and lung adenocarcinoma

    入江恭平, 入江恭平, 水野伸彦, 越宗靖二郎, 越宗靖二郎, 宮本朋幸, 宮本朋幸, 大塚愛二, 山本寛斉, 豊岡伸一, 増山寿, 小阪美津子

    日本がん転移学会学術集会・総会プログラム抄録集   30th   2021

  • 解剖研究を通じた超音波による長母指屈筋副頭の検出方法の改善

    坂口和輝, 坂口和輝, 中原龍一, 百田龍輔, 小阪美津子, 品岡玲, 大塚愛二

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   125th   2020

  • マウスとヒトにおけるPOU5F1遺伝子産物

    小阪美津子, 水野伸彦, 藤谷陽子, 藤谷陽子, 大塚愛二

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   125th   2020

  • ヒト腫瘍におけるPOU5F1とPOU5F1-PG1の役割の違い

    小阪美津子, 水野伸彦, 入江恭平, 大前凌, 大塚愛二

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   124th   2019

  • 眼:虹彩および網膜に存在する組織幹細胞の実態解明

    小阪美津子, 大塚愛二

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   122nd   2017

  • ヒトPOU5F1遺伝子ヴァリアントがコードするOCT4Cタンパク質の特性

    上園深希, 戎井孝太, 水野伸彦, 小阪美津子, 大塚愛二

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   122nd   2017

  • マウスOct3/4遺伝子variantがコードするOct3/4Cタンパク質の性状解析

    入江恭平, 水野伸彦, 小阪美津子, 小阪美津子, 大塚愛二

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   118th   2013

  • 体性組織で発現するOct3/4遺伝子variantの機能解析

    三宅望, 高畠あゆむ, 水野伸彦, 小阪美津子, 小阪美津子, 大塚愛二

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   118th   2013

  • ヒト癌細胞で発現するOct3/4遺伝子variantの同定

    宮本朋幸, 宮本朋幸, 水野伸彦, 大野英治, 大塚愛二, 小阪美津子, 小阪美津子

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   118th   2013

  • 微小血管内皮下弾性線維構造とその血行動態との関係

    品岡 玲, 百田 龍輔, 小阪 美津子, 内藤 一郎, 中原 龍一, 大塚 愛二

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   43回・58回   105 - 105   2011.5

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  • 組織を構成する個々の細胞の不均一性と可塑性

    小阪 美津子, 大塚 愛二

    解剖学雑誌   86 ( 1 )   19 - 19   2011.3

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  • Organ Biologyにおける再生医学の役割 体細胞のフレキシビリティの理解と応用

    小阪 美津子

    Organ Biology   15 ( 3 )   242 - 242   2008.10

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  • 遺伝子工学と組織再生 眼組織幹細胞としての虹彩上皮細胞の基礎と応用

    小阪 美津子

    Organ Biology   14 ( 3 )   235 - 235   2007.10

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  • 再生・組織形成・器官形成 生後マウス網膜における錐体-光受容体前駆細胞の発生学的可塑性(Developmental plasticity of cone-photoreceptor precursor cells in postnatal mouse retina)

    渡辺 康行, 浅見 真紀, Sun Guangwei, 土田 順司, 小阪 美津子

    日本発生生物学会・日本細胞生物学会合同大会要旨集   40回・59回   68 - 68   2007.5

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  • シグマ-1受容体はc-Jun N末端キナーゼ経路を介して皮質ニューロンの神経突起伸長と軸索形成を介在する(Sigma-1 receptor mediates neurite outgrowth and axon formation of cortical neurons via c-Jun N-terminal kinase pathway)

    油上 絵里, 渡邉 康行, 高山 美子, 三田 四郎, 小阪 美津子

    日本発生生物学会・日本細胞生物学会合同大会要旨集   40回・59回   180 - 180   2007.5

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  • TsukushiはWntシグナル伝達を阻害し、網膜幹細胞の増殖を制御する(Tsukushi inhibits Wnt signaling and regulates proliferation of retinal stem cells)

    伊藤 綾子, 栗山 正, 大沼 信一, 小阪 美津子, 中川 信一, 田中 英明, 太田 訓正

    日本発生生物学会・日本細胞生物学会合同大会要旨集   40回・59回   192 - 192   2007.5

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  • 視覚の発生・再生と神経保護 分子発生学・細胞生物学研究の新展開 眼組織幹細胞の起源と実態

    小阪 美津子

    日本眼科学会雑誌   110 ( 臨増 )   58 - 58   2006.3

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  • TsukushiはWnt2bと相互作用する網膜前駆細胞の分化を調節する(原標題は英語)

    伊藤綾子, 源島龍, 源島龍, 小阪美津子, 中川真一, 田中英明, 田中英明, 太田訓正, 太田訓正

    日本発生生物学会大会発表要旨集   39th   2006

  • Potential sources for retinal regeneration in mammals

    Mitsuko Kosaka, Maki Asami

    ZOOLOGICAL SCIENCE   22 ( 12 )   1376 - 1376   2005.12

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  • 成体組織幹細胞の可塑性 眼組織再生の理解と応用

    小阪 美津子

    日本発生生物学会大会講演要旨集   36回   38 - 38   2003.6

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  • ヒト培養網膜色素上皮細胞の神経細胞への分化

    雨宮 かおり, 春田 雅俊, 西田 明弘, 高橋 政代, 本田 孔士, 江口 吾郎, 小阪 美津子

    日本眼科学会雑誌   105 ( 臨増 )   254 - 254   2001.3

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  • Adult human retinal pigment epithelial cells can differentiate into neurone in vitro.

    K Amemiya, M Haruta, A Nishida, M Takahashi, Y Honda, G Eguchi, M Kosaka

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   42 ( 4 )   S779 - S779   2001.3

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  • 神経幹細胞を利用した神経網膜の再生の試み

    春田 雅俊, 西田 明弘, 高橋 政代, 本田 孔士, 小阪 美津子, 鐘ヶ江 裕美, 斉藤 泉

    日本眼科学会雑誌   105 ( 臨増 )   369 - 369   2001.3

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  • Induction of photoreceptor differentiation from retina-derived neural sphere with homeobox gene transfer.

    高橋政代, 赤木忠道, 春田雅俊, 秋田穣, 本田孔士, 小阪美津子, 鐘ケ江裕美, 斉藤泉

    網膜脈絡膜・視神経萎縮症調査研究班 平成12年度研究報告書   2001

  • 発生・再生を支える幹細胞システム 眼組織の再構築を支える幹細胞

    小阪 美津子

    日本発生生物学会大会講演要旨集   33回   6 - 6   2000.5

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  • Molecular analysis of lens transdifferentiation of pigmented epithelial cells

    M Kosaka, G Eguchi

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   40 ( 4 )   S926 - S926   1999.3

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  • Analysis of molecular mechanism of lens regeneration.

    小阪美津子, 江口吾朗

    日本発生生物学会大会発表要旨集   31回   150 - 150   1998.5

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  • EGF and/or bFGF induces lens transdifferentiation of retinal pigmented epithelial cells

    M Kosaka, G Eguchi

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   38 ( 4 )   147 - 147   1997.3

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  • 創傷治癒機序に基づくじょく創ケアの有効性

    藤沢三重子, 原田美津子, 今村美都子, 八木裕子, 伊藤朋枝, 内山美佳, 岡崎よしこ, 村田美恵子, 小阪マリ子

    日本社会保険医学会演説集   35th   1997

  • Lens transdifferentiation mechanisms of iris pigmented epithelial cells.

    小阪美津子, 江口吾朗

    日本発生生物学会大会発表要旨集   29th   1996

  • マウステラトカルシノーマF9細胞の可逆的分化誘導

    小阪 美津子

    日本発生生物学会大会講演要旨集   23回   125 - 125   1990.5

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  • マウステラトカルシノーマF9細胞のNa-butyrateによる可逆的分化誘導について

    小阪 美津子

    日本癌学会総会記事   48回   148 - 148   1989.10

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  • マウステラトカルシノーマの自己増殖から分化決定への過程におけるoncogeneの発現 細胞分化に関する変異株を用いた解析

    小阪 美津子

    日本発生生物学会大会講演要旨集   22回   108 - 108   1989.6

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  • ANALYSIS OF TS MUTANTS OF CELL-DIFFERENTIATION IN EC CELLS

    M KOSAKA, Y NISHINA, Y NISHIMUNE

    DEVELOPMENT GROWTH & DIFFERENTIATION   30 ( 4 )   417 - 417   1988.8

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Presentations

  • マウスとヒトにおけるPOU5F1遺伝子産物

    小阪美津子・水野伸彦・大前凌・入江恭平・大塚愛二

    第125回日本解剖学会総会・全国学術集会  2020.3 

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    Event date: 2020.3.27 - 2020.3.29

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    Venue:新潟  

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  • 解剖研究を通じた超音波による長母指屈筋副頭の検出方法の改善

    坂口 和輝、中原 龍一、百田 龍輔、小阪 美津子、品岡 玲、大塚 愛二

    第125回日本解剖学会総会・全国学術集会  2020.3 

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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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  • Conclusive evidence for OCT4 transcription in human cancer cell lines: possible role of a small OCT4-positive cancer cell population

    Tomoyuki Miyamoto, Nobuhiko Mizuno, Aiji Ohtsuka, Mitsuko Kosaka

    第41回日本分子生物学会年会  2018.11 

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    Event date: 2018.11.28 - 2018.11.30

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  • ヒトがん細胞で発現す る OCT4転写 ・ 翻訳産物の同定と機能解析

    小阪美津子、水野伸彦、宮本朋幸、藤谷陽子、大塚愛二

    日本解剖学会第73回中国・四国支部学術集会  2018.10 

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    Event date: 2018.10.20 - 2018.10.21

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  • 医療専門職教育における解剖実習の現状と課題:岡山大学の場合

    大塚愛二、百田龍輔、小阪美津子、品岡玲、田口勇仁

    日本解剖学会第72回中国・四国支部学術集会  2017.10 

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    Event date: 2017.10.28 - 2017.10.29

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  • 虹彩および網膜に存在する組織幹細胞の実態解明

    小阪美津子・大塚愛二

    第122回日本解剖学会総会・全国学術集会・シンポジウム  2017.3 

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    Event date: 2017.3.28 - 2017.3.30

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:長崎大学  

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  • ヒトPOU5F1 遺伝子ヴァリアントがコードするOCT4Cタンパク質の特性

    上園 深希、戎井 孝太、水野 伸彦、小阪 美津子、大塚 愛二

    第122回日本解剖学会総会・全国学術集会  2017.3 

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    Event date: 2017.3.28 - 2017.3.30

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    Venue:長崎大学  

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  • ヒトOct4遺伝子とOct4偽遺伝子の機能的差異

    戎井孝太、小阪美津子、水野伸彦、大塚愛二

    日本解剖学会第70回中国・四国支部学術集会(愛媛)  2015.10 

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    Event date: 2015.10.24 - 2015.10.25

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  • 悪性度の異なる2種類のヒト乳がん細胞の性状比較

    大谷啓江, 小阪美津子, 水野伸彦, 宮本朋幸, 大塚愛二

    第2回中四国医学部生研究集会  2015.1 

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  • ヒトの手の小動脈壁における弾性線維構築の走査型電子顕微鏡観察

    木戸真由子, 品岡玲, 百田龍輔, 小阪美津子, 大塚愛二

    日本解剖学会第69回中国・四国支部学術集会  2014.10 

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    Event date: 2014.10.25 - 2014.10.26

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:広島  

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  • 万能遺伝子プロモーターの新規開発

    小阪美津子

    岡山リサーチパーク合同研究発表会  2014.9 

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    Event date: 2014.9.4

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  • ヒトOCT4遺伝子発現解析における問題点の克服

    宮本朋幸、小阪美津子、水野伸彦、大野英治、大塚愛二

    日本解剖学会第68回中国四国支部学術集会  2013.10 

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    Event date: 2013.10.19 - 2013.10.20

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • 体性組織で発現するマウスOct3/4遺伝子variant蛋白質の機能解析

    三宅望、高畠あゆむ、水野伸彦、小阪美津子、大塚愛二

    第118回日本解剖学会総会・全国学術集会  2013.3 

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    Event date: 2013.3.28 - 2013.3.30

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  • ヒト癌細胞で発現するOct3/4遺伝子variant型の同定

    宮本朋之、水野伸彦、大野英治、大塚愛二、小阪美津子

    第118回日本解剖学会総会・全国学術集会  2013.3 

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    Event date: 2013.3.28 - 2013.3.30

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  • マウスOct3/4遺伝子variantがコードするC型蛋白質の性状解析

    入江恭平、水野伸彦、小阪美津子、大塚愛二

    第118回日本解剖学会総会・全国学術集会  2013.3 

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    Event date: 2013.3.18 - 2013.3.30

    Language:Japanese   Presentation type:Poster presentation  

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  • 食道の後ろを通る左鎖骨下動脈を伴う右側大動脈弓の一例

    黒田和弘、入江恭平、楢崎正博、百田龍輔、小阪美津子、大塚愛二

    日本解剖学会第67回中四国支部会  2012.10 

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    Event date: 2012.10.20 - 2012.10.21

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • 微小血管内皮下繊維構造とその血行動態との関係

    品岡玲、百田龍輔、小阪美津子、内藤一郎、中原龍一、大塚愛二

    第43回日本結合組織学会学術大会・第58回マトリックス研究会大会合同学術集会  2012.6 

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    Event date: 2012.6.11

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • 転写調節因子Oct3/4-A,B,Cの性状比較

    高畠あゆむ、小阪美津子、水野伸彦、大塚愛二

    岡山医学会  2012.6 

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    Event date: 2012.6.7

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

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  • Neural stem/progenitor cells in the iris tissues of the chick embryo International conference

    M Araki, T Ishikawa, A Fujihara and M Kosaka

    Joint Meeting of JSDB 45th and JSCB 64th at Kobe in 2012  2012.5 

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    Event date: 2012.5.29 - 2012.5.31

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  • 微小血管の内皮下弾性線維の操作電子顕微鏡観察?血管の種類とサイズに応じての変化?

    品岡玲、百田龍輔、中原龍一、内藤一郎、熊岸加苗、小阪美津子、大塚愛二

    第117回日本解剖学会総会・全国学術集会 

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    Event date: 2012.3.26 - 2012.3.28

    Language:Japanese   Presentation type:Poster presentation  

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  • Transdifferentiation of neuronal cells from iris pigment epithelial cells International conference

    Tamami Ishikawa, Mitsuko Kosaka and Masasuke Araki

    44th Annual Meeting of the Japanese Society of Developmental Biologists/ Asia-Pacific Developmental Biology Network 

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    Event date: 2011.5.18 - 2011.5.21

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  • 組織を構成する個々の細胞の不均一性と可塑性

    小阪美津子、大塚愛二

    日本解剖学会第65回中四国支部会  2010.10 

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    Event date: 2010.10.6 - 2010.10.7

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  • 子宮内膜癌および肺腺癌細胞におけるOCT4A/SPP1C共発現とその臨床的意義

    入江恭平, 水野伸彦, 越宗靖二郎, 宮本朋幸, 大塚愛二, 山本寛斉, 豊岡伸一, 増山寿, 小阪美津子

    第30回日本がん転移学会学術集会・総会  2021.7.29 

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  • ヒト腫瘍におけるPOU5F1とPOU5F1PG1の役割の違い

    小阪美津子, 水野伸彦, 入江恭平, 大前凌, 大塚愛二

    第124回日本解剖学会総会・全国学術集会  2019.3 

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Awards

  • (公益財団法人)がん研究振興財団 研究奨励賞

    2019.4  

  • 両備てい園記念財団 生物学に係る研究奨励賞

    2005.7  

  • 岡山県ベンチャープランコンテスト 審査員特別賞

    2004.9  

  • (公益財団法人)大阪対がん協会 研究奨励賞

    1993.3  

Research Projects

  • 転移の鍵をにぎるSPP1遺伝子発現制御機構の解明とその応用

    Grant number:19K09287  2019.04 - 2022.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    小阪 美津子

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

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  • Cellular plasticity of OCT4 expressing somatic cells

    Grant number:15K15016  2015.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    KOSAKA MITSUKO, MIZUNO NOBUHIKO

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    Grant amount:\3770000 ( Direct expense: \2900000 、 Indirect expense:\870000 )

    Oct4A, a POU-family transcription factor, is an indispensable and the preeminent pluripotency factor. However, whether Oct4 function in somatic tissues remains debated. Here we tried some useful systems to correctly understand somatic OCT4 gene function. Our findings open up the possibility again that OCT4 can be normal tissue stem cells and/or tumor initiating cells marker and could play a pivotal role in somatic tissues. In this study, we identified and characterized OCT4 transcripts and their translation products in human carcinoma cell lines.

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  • Role of Oct3/4 in retinal development and dieseases

    Grant number:23592606  2011 - 2013

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    KOSAKA MITSUKO, MIZUNO Nobuhiko, OHTUKA Aiji

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    Grant amount:\5460000 ( Direct expense: \4200000 、 Indirect expense:\1260000 )

    We tried to investigate roles of Oct3/4 gene during development of normal retina and retinal diseases including tumors. At the first step, we re-investigated Oct3/4 expression in mouse eye. We isolated a novel Oct3/4 variant from normal mouse retina, which is regulated under translational control. Using human retinoblastoma and other carcinoma cell lines, we tested the expression of Oct3/4 transcripts and identified a variety of novel ones. Our results showed the clear different pattern between mice and human Oct3/4 gene variants expression, providing available relevant information for understanding the function of Oct3/4 in somatic tissue.

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  • Key genes related to retinal development and diseases

    Grant number:19592048  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    KOSAKA Mitsuko, MIZUNO Nobuhiko

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    Grant amount:\4550000 ( Direct expense: \3500000 、 Indirect expense:\1050000 )

    幼弱期のマウス網膜組織内に、光受容体細胞(視細胞)の形質を獲得しているにもかかわらず、取り出して培養すると増殖を開始して他の網膜神経細胞へ分化転換するという細胞を発見した。その細胞は組織傷害時などに細胞分裂を開始し他の神経を生み出す幹細胞として機能しうる可能性が器官培養系の結果から得られ、全く新規の網膜幹細胞であることが示唆された。またその細胞の遺伝子発現を網羅的に解析し、網膜の発生・分化・疾患に関わる遺伝子候補を多数同定した。

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  • MOLECULAR MECHANISMS UNDERLYING THE MULTIPOTENCY OF DIFFERENTIATED PIGMENTED EPITHELIAL CELLS.

    Grant number:09680733  1997 - 1998

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    MOCHII Makoto, KOSAKA Mitsuko

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    Grant amount:\3300000 ( Direct expense: \3300000 )

    Vertebrate pigmented epithelial cells (PECs) are unique in their ability to transdifferentiate to lens and neural retinal cells.To elucidate the molecular mechanisms underlying the multi-potency of PECs, we focused on the role and regulation of Mitf, a basic-helix-loop-helix-zipper transcriptional factor.
    Chicken Mitf is first detected in the proximal region of the optic vesicle, a presumptive pigmented epithelium, at a stage when no other markers for PECs are detected.The expression increases according to the PEC differentiation both in vivo and in vitro.Mitf expression is down-regulated by FGF and EGF treatments, which induce dedifferentiation and transdifferentiation.Overexpression of Mitf using a retrovirus vector supports expression of pigment cell specific genes, mmpll5 and tyrosinase, and inhibits transdifferentiation
    We found that a silver mutation in Japanese quail is caused by a loss-of-function mutation in the Mitf.A part of PECs in the silver quail spontaneously transdifferentiate to neural retinal cells in vivo.Isolated PECs from the silver mutant frequently transdifferentiate to both lens and neural cells in vitro with no addition of growth factors, while either FGF or EGF is required for wild type PECs to transdifferentiate.
    These results demonstrate that Mitf has a critical role in regulation of transdifferentiation and suggest that the regulational mechanism for Mitf expression should be analysed to reveal the molecular mechanisms underlying the multi-potency OF pigmented epithelial cells.

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  • Molecular Mechanism of Transdifferentiation in Regeneration

    Grant number:07044210  1995 - 1997

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for international Scientific Research  Grant-in-Aid for international Scientific Research

    KODAMA Ryuji, TSONIS Panagiotis, MOCHII Makoto, EGUCHI Goro

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    Grant amount:\11000000 ( Direct expense: \11000000 )

    Since this year is the last year of our collaborative studies, we concentrate our effort to the studies using urodelan amphibian species, Cynopus pyrrhogaster, the Japanese newt, and unstudied problems about the lens regeneration phenomenon, i.e. i) relationship between the aging of the iris pigmented epithelium and its regenerative ability to produce a new lens, ii) molecular basis of the localization of lens regenerative potency to the dorsal margin of the iris, and iii) expression pattern of the genes which are important in the early embryogenesis processes during the lens regeneration process in the adult iris.
    i) We have induced continuous cell proliferation in the iris pigmented epithelial cells by successive surgeries of removing the lens from the same eye. After about 10th operations, we have observed a conspicuous delay in the process of the lens regeneration. This observation strongly suggests that the aging of the iris pigmented epithelial cells, which give rise to the regeneration of the lens, may finally results in the loss of the potency of the lens regeneration.
    ii) When the FGF,fibroblst growth factor, is continuously injected in excessive amount into the eye, the lens regeneration besides the dorsal most iris was induced. This result suggests that the stimulation of the FGF receptor may induce the inhibition of lens regeneration processes.
    iii) Genes which have been indicated to take important roles in the tissue interactions in the early embryogenesis, such as pax-6, FGF-1, FGFR-1, FGFR-2, FGFR-3, prox-1, and ssh, were also evidenced to show characteristic expression patterns in the lens regeneration processes. This suggests that these genes are important in the regulation of tissue interactions in the lens regeneration processes.
    Results indicated above are new and important results. The result i) has prompted us to start preparation of a set of newt individuals which are raised from fertilized eggs and have definitive record to their age, which makes it possible to study the relationship between aging and the lens regeneration potency more thoroughly. We have also started the analyzes at the level of the genes concerning the result ii). Part of the result iii) have already published. The results obtained in this year have, thus, made it possible to start a new series of investigations with higher scientific significance.

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  • Molecular Mechanisms of Transdifferentiation and Stabilization in Differentiation of Animal Tissue Cells

    Grant number:07458197  1995 - 1996

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    EGUCHI Goro, KOSAKA Mitsuko, MOCHII Makoto, KODAMA Ryuji

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    Grant amount:\7100000 ( Direct expense: \7100000 )

    The following results were obtained by conducting the research plans in 1996.
    (1) Through extensive studies to improve our authentic in vitro transdifferentiation system of retinal pigmented epithelial cells (PECs) from 8 to 10-day-old chick embryos, both bFGF were found to be essential factors regulating transdifferentiation of PECs. In addition, by introducing these tow growth factors to cell cultures, we succeeded in establishing a novel and highly stable in vitro experimental system of the iris PECs from neuwly-hatched chicks. The system allows us to manipulate the whole process of the lens transdifferentiation of PECs without any artificial reagent.
    (2) Analyzes using this system revealed that activation of MAP kinase is an essential requisite for dedif-ferentiation of PECs and that the expression of two homeobox genes, pax6 and six3 are dramatically enhanced by coordinated functions of bFGF and EGF.
    (3) The following results were obtained through detailed analysis of changes in the extracellular matrix (ECM) during transdifferentiation of PECs that beta1 integrin plays an essential role in stable maintenance of the differentiated state of PECs by transmitting signals from ECM components to PECs, and that beta1 integrin molecules are readily phospholylated to lose their function when dedifferentiation of PECs is initiated.
    (4) It was resulted in by cloning and structural and functional analysis of avian microphthalmia gene (mi) that mutation of mi must be responsible for ectopic formation of the neural retina from the developing pigmented epithelium in Silver mutant of the quail, and also that mi is one of essential genes, which regulate dedifferentiation and transdifferentiation of the vertebrate PEC.
    (5) These findings must provide the fundamental information required for approaching to the molecular mechanisms involved in transdifferentiation and stability in differentiation of tissue cells in general.

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  • 虹彩色素上皮細胞によるレンズ細胞への分化転換機構

    Grant number:07780668  1995

    日本学術振興会  科学研究費助成事業 奨励研究(A)  奨励研究(A)

    小阪 美津子

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    Grant amount:\1000000 ( Direct expense: \1000000 )

    ニワトリ(孵化後1-2日)の眼球より虹彩色素上皮細胞を分離し培養を行い、色素細胞の分化状態を安定に維持する条件、及びレンズ細胞へ効率よく分化転換させうる最適条件を決定することができた(国際学術誌に投稿準備中)。今回得られた虹彩色素上皮培養系はその安定性、再現性、分化転換効率が、従来の網膜色素上皮細胞培養系に比べ非常に高く、レンズ再生の分子機構の解明に優れたモデル系となり得ると考えられた。
    色素上皮細胞がレンズ細胞へ分化転換する過程において、bFGF(basic fibloblast growth factorは必須の因子であり、色素上皮細胞の脱分化過程、レンズ細胞への再分化過程の双方のステップにおいて重要な働きを持つことが示唆された。さらに、各種増殖関連因子を培養系に添加しその影響を検討した結果、EGF(epidermal growth factor)が虹彩色素上皮細胞の分化状態に著名な変化を及ぼすことが初めて明らかとなった。予備的実験から、EGFは虹彩色素上皮細胞の脱分化を促進する可能性が示唆され、この因子の分化転換過程での働きを明らかにするとともに、生体でのレンズ再生過程におけるEGFの関与についても現在解析中である。
    上記のニワトリ色素上皮細胞による分化転換過程の解析を行うと共に、トランスジェニック実験系が確立しているマウスにおいても虹彩色素上皮細胞の培養を試みた。その結果、野生型マウス由来の色素上皮細胞は早い段階で増殖が停止し株化は困難であったが、ガン抑制遺伝子P35分子の遺伝子をジーンターゲット法により破壊したマウス(p53ノックアウトマウス)由来のものでは、長期間培養が可能で、10数種の独立した細胞株をクローニングすることに成功した。現在、これらの細胞株についての性状分析を行っている。

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