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MORIYAMA Hiroyuki

    Pharmaceutical Research and Technology Institute　Associate Professor
Last Updated :2024/04/25

Researcher Information

Degree

  • Ph.D.（Kyoto Univ.）

J-Global ID

Research Areas

  • Life sciences / Medical biochemistry
  • Life sciences / Dermatology
  • Life sciences / Cell biology
  • Other / Other

Academic & Professional Experience

  • 2010 - Today  KINDAI UNIVERSIYPharmaceutical Research and Technology Institute准教授

Association Memberships

  • THE JAPANESE SOCIETY FOR INVESTIGATIVE DERMATOLOGY   International Society for Stem Cell Research   THE MOLECULAR BIOLOGY SOCIETY OF JAPAN   THE JAPANESE SOCIETY FOR REGENERATIVE MEDICINE   

Published Papers

  • Hiroyuki Moriyama; Mariko Moriyama; Toshiyuki Ozawa; Daisuke Tsuruta; Takao Hayakawa
    Cell journal 24 (12) 705 - 714 2022/12 
    OBJECTIVE: Human adipose-derived mesenchymal stromal/stem cells (hASC) constitute an attractive source of stem cells for cell-based therapies in regenerative medicine and tissue engineering as they are easy to acquire from lipoaspirate, expansion, and genetic modification ex vivo. The combination of Pdx-1, MafA, and NeuroD1 has been indicated to possess the ability to reprogram various types of cells into insulin-producing cells. The aim of this study is to investigate whether MafA and NeuroD1 would cooperate with Pdx-1 in the differentiation of hASC into insulin-producing cells. MATERIALS AND METHODS: In this experimental study, we generated polycistronic expression vectors expressing Pdx1 and MafA/NeuroD1 with a reporter from a human EF-1α promoter using 2A peptides in a single tet-off lentiviral vector system. Briefly, hASC were transduced with the lentiviral vectors and allowed to differentiate into insulin-producing cells in vitro and in vivo. Thereafter, RNA expression, dithizone staining, and immunofluorescent analysis were conducted. RESULTS: Cleaved transcriptional factors from a single tet-off lentiviral vector were functionally equivalent to their native proteins and strictly regulated by doxycycline (Dox). Insulin gene expression in hASC transduced with Pdx1, Pdx1/ MafA, and Pdx1/NeuroD1 in differentiation medium were successfully increased by 1.89 ± 0.39, 4.81 ± 0.98, 5.51 ± 0.63, respectively, compared to venus-transduced, control hASC. These cells could form dithizone-positive cell clusters in vitro and were found to express insulin in vivo. CONCLUSION: Using our single tet-off lentiviral vector system, Pdx-1 and MafA/NeuroD1 could be simultaneously expressed in the absence of Dox. Further, this system allowed the differentiation of hASC into insulin-producing cells.
  • Nobuaki Okumura; Takashi Ito; Tomomi Degawa; Mariko Moriyama; Hiroyuki Moriyama
    International Journal of Molecular Sciences MDPI AG 22 (23) 12973 - 12973 2021/11 [Refereed]
     
    Royal jelly (RJ) is secreted by honeybees and has been used as an apitherapy to obtain healthy skin since ancient times. However, the mechanism of the protective effects of RJ against skin aging and skin diseases caused by skin stress and its components have not been clarified. In this study, we attempted to understand the effect of RJ on epidermal function and observed that NAD(P)H quinone dehydrogenase 1 (NQO1) is significantly induced by RJ in keratinocytes. The expression of NQO1 was also increased in the 3D epidermal skin model. NQO1 is involved in antioxidation and detoxification metabolism, and we found that RJ protects against the epidermal stress caused by UVB and menadione through the upregulation of NQO1. We identified 10-hydroxy-2-decenoic acid (10H2DA), a major fatty acid in RJ, as an active compound in this reaction as it induced the expression of NQO1 and protected the skin against oxidative stress. We demonstrated that the protective effect of RJ against epidermal stress is mediated through the upregulation of NQO1 by 10H2DA.
  • Ato Daijiro; Hirose Takashi; Yoshida Akihiko; Onimoto Akane; Shimizu Tadashi; Tokai Hidekichi; Inoue Tomomi; Yatsushiro Tetsuya; Kotake Takeshi; Komori Koji; Moriyama Hiroyuki; Mitamura Shinobu; Hidaka Mari; Mizuno Naoko
    Japanese Journal of Pharmaceutical Education Japan Society for Pharmaceutical Education 5 (別刷) n/a - 90 2432-4124 2021/02 [Refereed]
     

    Given the rapid spread of COVID-19, the case analysis debriefing session during pharmacy practice was changed from a group format to an online format. This report provides an overview of the online format of case analysis debriefing. In addition, we discuss the benefits and problems of the debriefing session that were revealed by the questionnaire survey. The online debriefing sessions were conducted by connecting trainees and evaluators from Osaka General Hospital of West Japan Railway Company via Zoom during the 6th and 11th weeks of practice. Most participants (83%) approved of the online debriefing sessions because of the ease of participation and time advantage. However, some participants disapproved due to the lack of realism and communication between participants in the group training. The online format is considered a very effective educational tool in a collaborative hospital-pharmacy-university setting. However, it was suggested that challenges remain with the online format, such as whether participants can create as much of an atmosphere as in the group format.

  • Ato Daijiro; Yoshida Akihiko; Onimoto Akane; Yatsushiro Tetsuya; Ohara Takashi; Shimizu Tadashi; Tokai Hidekichi; Kotake Takeshi; Komori Koji; Moriyama Hiroyuki; Inoue Tomomi; Mitamura Shinobu; Hidaka Mari; Mizuno Naoko; Hirose Takashi
    Japanese Journal of Pharmaceutical Education Japan Society for Pharmaceutical Education 4 163 - 170 2432-4124 2021/01 [Refereed]
     

    This study examined how a joint pharmacy-hospital education program using an original Prescriptions Analysis Report influenced trainees' prescription analysis ability during practical training. The prescription analysis report comprises of four main criteria, including the reason for selecting the case, the information gathered from prescriptions and medication history, the prescription analysis results, and personal impressions of the prescription analysis. The trainees submitted at least one report per week and presented the information with a discussion in the first, sixth, and eleventh weeks of the training. Pharmacists and faculty members on the evaluation team used a rubric to assess the submitted reports and presentations. The results showed that the ability to analyze prescriptions significantly improved in the eleventh week compared to that in the first and sixth weeks for all prescription analysis criteria, especially the ability to select cases based on disease awareness. The trainee responses on a questionnaire indicated that the program helped them develop more skills but raised issues with the feedback method after the presentations.

  • Tien Minh Le; Naoki Morimoto; Nhung Thi My Ly; Toshihito Mitsui; Sharon Claudia Notodihardjo; Maria Chiara Munisso; Natsuko Kakudo; Hiroyuki Moriyama; Tetsuji Yamaoka; Kenji Kusumoto
    Scientific reports 10 (1) 17594 - 17594 2020/10 [Refereed]
     
    We previously showed that high hydrostatic pressure (HHP) treatment at 200 MPa for 10 min induced complete cell death in skin and skin tumors via necrosis. We used this technique to treat a giant congenital melanocytic nevus and reused the inactivated nevus tissue as a dermis autograft. However, skin inactivated by HHP promoted inflammation in a preclinical study using a porcine model. Therefore, in the present study, we explored the pressurization conditions that induce apoptosis of the skin, as apoptotic cells are not believed to promote inflammation, so the engraftment of inactivated skin should be improved. Using a human dermal fibroblast cell line in suspension culture, we found that HHP at 50 MPa for ≥ 36 h completely induced fibroblast cell death via apoptosis based on the morphological changes in transmission electron microscopy, reactive oxygen species elevation, caspase activation and phosphatidylserine membrane translocation. Furthermore, immunohistochemistry with terminal deoxynucleotidyl transferase dUTP nick-end labeling and cleaved caspase-3 showed most cells in the skin inactivated by pressurization to be apoptotic. Consequently, in vivo grafting of apoptosis-induced inactivated skin resulted in successful engraftment and greater dermal cellular density and macrophage infiltration than our existing method. Our finding supports an alternative approach to hydrostatic pressure application.
  • Jun Teishima; Daiki Murata; Shogo Inoue; Tetsutaro Hayashi; Koji Mita; Yasuhisa Hasegawa; Masao Kato; Mitsuru Kajiwara; Masanobu Shigeta; Satoshi Maruyama; Hiroyuki Moriyama; Seiji Fujiwara
    Molecular and clinical oncology 12 (6) 557 - 564 2020/06 
    The present study investigated the outcomes of targeted therapy for elderly patients with metastatic renal cell carcinoma (mRCC). A total of 277 patients with mRCC who were treated with tyrosine kinase inhibitor as a first-line therapy from January 2008 to May 2018 were retrospectively investigated by reviewing clinicopathological data. Patients 75 years or older were classified into the older-aged group (n=55) while all others were classified into the younger-aged group (n=222). The preoperative clinicopathological characteristics and the overall survival (OS) rate for these two groups were subsequently compared. The median age in the older- and younger-aged groups was 78 and 63 years (P<0.0001), respectively. A total of 7, 42 and 6 cases in the older-aged group and 46, 118 and 58 cases in the younger-aged group were classified into favorable, intermediate, and poor risk groups, respectively. The rate of patients with cardiovascular diseases (29.1%) and malignant diseases other than RCC (20.0%) was significantly higher in the older-aged group compared with the younger-aged group (6.8%; P<0.0001 and 7.2%; P=0.0042, respectively). There was a significant improvement in the OS rate for patients beginning targeted therapy after 2011 compared with those starting therapy prior to 2010. The 50% OS rate in patients starting targeted therapy before 2010 and after 2011 was, respectively, 17.1 and 38.6 months for the older-aged group (P=0.0066), while there was no significant difference for the younger-aged group (P=0.1441; 50% OS; 35.9 vs. 30.5 months). The results of the present study indicated that the prognosis for older patients has improved since the introduction of targeted therapy.
  • Toshihito Mitsui; Naoki Morimoto; Atsushi Mahara; Sharon Claudia Notodihardjo; Tien Minh Le; Maria Chiara Munisso; Mariko Moriyama; Hiroyuki Moriyama; Natsuko Kakudo; Tetsuji Yamaoka; Kenji Kusumoto
    BioMed research international 2020 9478789 - 9478789 2020 [Refereed]
     
    High hydrostatic pressure (HHP) is a physical method for inactivating cells or tissues without using chemicals such as detergents. We previously reported that HHP at 200 MPa for 10 min was able to inactivate all cells in skin and giant congenital melanocytic nevus (GCMN) without damaging the extracellular matrix. We also reported that HHP at 150 MPa for 10 min was not sufficient to inactivate them completely, while HHP at 200 MPa for 10 min was able to inactivate them completely. We intend to apply HHP to treat malignant skin tumor as the next step; however, the conditions necessary to kill each kind of cell have not been explored. In this work, we have performed a detailed experimental study on the critical pressure and pressurization time using five kinds of human skin cells and skin tumor cells, including keratinocytes (HEKas), dermal fibroblasts (HDFas), adipose tissue-derived stem cells (ASCs), epidermal melanocytes (HEMa-LPs), and malignant melanoma cells (MMs), using pressures between 150 and 200 MPa. We pressurized cells at 150, 160, 170, 180, or 190 MPa for 1 s, 2 min, and 10 min and evaluated the cellular activity using live/dead staining and proliferation assays. The proliferation assay revealed that HEKas were inactivated at a pressure higher than 150 MPa and a time period longer than 2 min, HDFas and MMs were inactivated at a pressure higher than 160 MPa and for 10 min, and ASCs and HEMa-LPs were inactivated at a pressure higher than 150 MPa and for 10 min. However, some HEMa-LPs were observed alive after HHP at 170 MPa for 10 min, so we concluded that HHP at a pressure higher than 180 MPa for 10 min was able to inactivate five kinds of cells completely.
  • Mariko Moriyama; Shunya Sahara; Kaori Zaiki; Ayumi Ueno; Koichi Nakaoji; Kazuhiko Hamada; Toshiyuki Ozawa; Daisuke Tsuruta; Takao Hayakawa; Hiroyuki Moriyama
    Scientific reports 9 (1) 18371 - 18371 2019/12 [Refereed]
     
    Wound healing is regulated by complex interactions between the keratinocytes and other cell types including fibroblasts. Recently, adipose-derived mesenchymal stromal/stem cells (ASCs) have been reported to influence wound healing positively via paracrine involvement. However, their roles in keratinocytes are still obscure. Therefore, investigation of the precise effects of ASCs on keratinocytes in an in vitro culture system is required. Our recent data indicate that the epidermal equivalents became thicker on a collagen vitrigel membrane co-cultured with human ASCs (hASCs). Co-culturing the human primary epidermal keratinocytes (HPEK) with hASCs on a collagen vitrigel membrane enhanced their abilities for cell proliferation and adhesion to the membrane but suppressed their differentiation suggesting that hASCs could maintain the undifferentiated status of HPEK. Contrarily, the effects of co-culture using polyethylene terephthalate or polycarbonate membranes for HPEK were completely opposite. These differences may depend on the protein permeability and/or structure of the membrane. Taken together, our data demonstrate that hASCs could be used as a substitute for fibroblasts in skin wound repair, aesthetic medicine, or tissue engineering. It is also important to note that a co-culture system using the collagen vitrigel membrane allows better understanding of the interactions between the keratinocytes and ASCs.
  • Hiroyuki Moriyama; Mariko Moriyama; Toshiyuki Ozawa; Daisuke Tsuruta; Taro Iguchi; Satoshi Tamada; Tatsuya Nakatani; Koichi Nakagawa; Takao Hayakawa
    Stem cells and development 27 (13) 935 - 947 1547-3287 2018/07 [Refereed]
     
    Human adipose-derived mesenchymal stromal cells (hASCs) are attractive for regenerative medicine, but their limited in vitro life span limits their therapeutic applicability. Recent data demonstrate that hypoxia may benefit the ex vivo culture of stem cells. Such cells exhibit a high level of glycolytic metabolism under hypoxic conditions. However, the physiological role of glycolytic activation and its underlying regulatory mechanism are incompletely understood. We have shown that when activated under conditions of 5% O2, Notch signaling dramatically increases the rate of glycolysis, improves proliferation efficiency, prevents senescence, and maintains the multipotency of hASCs. In the present study, we found that activated Notch1 enhanced nuclear p65 levels, resulting in an increase in glucose metabolism through the upregulation of glycolytic factors, including GLUT3. Notch signaling was also involved in glucose metabolism through p53 inactivation. We also found that NF-κB signaling was regulated by p53. These data suggest that Notch-HES1 signaling enhances the glycolytic pathway through p53 and NF-κB. Our data also revealed that activated Notch1 markedly increased the transcriptional activity of hypoxia-inducible factor 1 (HIF-1). Knockdown of HIF-1α significantly attenuated glycolysis induced by activated Notch1, indicating that the glycolysis pathway is regulated by the coordination of Notch signaling and HIF. Overall, our observations provide new regulatory mechanisms for the glycolysis by Notch signaling to maintain the stemness of hASCs.
  • 薬学部実務実習生を対象にした処方解析プログラムの効果の検証について
    齋藤 玲奈; 阿登 大次郎; 清水 忠; 森山 博由; 小竹 武; 井上 知美; 小森 浩二; 三田村 しのぶ; 日高 眞理; 廣瀬 隆; 吉田 彰彦; 小牟田 豊; 東海 秀吉
    日本交通医学会 72 (1-2) 17 - 17 2018/03 [Refereed]
  • Satoh Ryosuke; Hagihara Kanako; Matsuura Kazuki; Manse Yoshiaki; Kita Ayako; Kunoh Tatsuki; Masuko Takashi; Moriyama Mariko; Moriyama Hiroyuki; Tanabe Genzoh; Muraoka Osamu; Sugiura Reiko
    Genes to cells : devoted to molecular & cellular mechanisms 22 (7) 608-618 - 618 1365-2443 2017/07 [Refereed]
     
    Here, we carried out a chemical genetic screen using a fission yeast phenotypic assay and showed that ACA-28, a synthetic derivative of 1'-acetoxychavicol acetate (ACA), which is a natural ginger compound, effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. ACA-28 more potently inhibited the growth of melanoma cells than did the parental compound ACA. Importantly, the growth of normal human epidermal melanocytes (NHEM) was less affected by ACA-28 at the same 50% inhibitory concentration. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells which were oncogenically transformed with human epidermal growth factor receptor-2 (HER2/ErbB2), but not in the parental cells. ACA-28 might serve as a promising seed compound for melanoma treatment.
  • Mariko Moriyama; Hiroyuki Moriyama; Junki Uda; Hirokazu Kubo; Yuka Nakajima; Arisa Goto; Takashi Morita; Takao Hayakawa
    Cell death & disease (一社)日本研究皮膚科学会 8 (2) e2576 - 200 2041-4889 2017/02 [Refereed]
     
    The human skin has an important role in barrier function. Ultraviolet rays (UV) from sunlight exposure can cause cell apoptosis in the skin epidermis, resulting in the disruption of the barrier. Previously, we have demonstrated that BNIP3 stimulates autophagy in epidermal keratinocytes and has a protective effect in these cells upon UVB irradiation. In this study, we found that the accumulation of reactive oxygen species (ROS) by UVB irradiation was sufficient to trigger the activation of JNK and ERK mitogen-activated protein kinase (MAPK) in human primary epidermal keratinocytes. In turn, activated JNK and ERK MAPK mediated the upregulation of BNIP3 expression. Treatment with an antioxidant reagent or a specific inhibitor of MAPK, U0126, and a JNK inhibitor significantly attenuated the expression of BNIP3 triggered by UVB, followed by the induction of cell death by apoptosis. Furthermore, UVB-induced apoptosis was significantly stimulated by chloroquine or bafilomycin A1, an inhibitor of autophagy. Moreover, BNIP3 was required for the degradation of dysfunctional mitochondria upon UVB irradiation. These data clearly indicated that BNIP3-induced autophagy, which occurs via UVB-generated ROS-mediated JNK and ERK MAPK activation, has a crucial role in the protection of the skin epidermis against UVB irradiation.
  • Isao Kobayashi; Fumiyuki Takahashi; Fariz Nurwidya; Takeshi Nara; Muneaki Hashimoto; Akiko Murakami; Shigehiro Yagishita; Ken Tajima; Moulid Hidayat; Naoko Shimada; Kentaro Suina; Yasuko Yoshioka; Shinichi Sasaki; Mariko Moriyama; Hiroyuki Moriyama; Kazuhisa Takahashi
    Biochemical and biophysical research communications ACADEMIC PRESS INC ELSEVIER SCIENCE 473 (1) 125 - 132 0006-291X 2016/04 [Refereed]
     
    Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC cells with an activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9, which express the EGFR exon 19 deletion mutation, were transplanted into NOG mice, and were treated with gefitinib in vivo. After 14-17 days of gefitinib treatment, the tumors still remained; these tumors were referred to as gefitinib-resistant tumors (GRTs). PC9-GRTs showed higher expression of Oct4 and CD133. To investigate the role of Oct4 in the maintenance of gefitinib-resistant lung CSCs, we introduced the Oct4 gene into PC9 and HCC827 cells carrying an activating EGFR mutation by lentiviral infection. Transfection of Oct4 significantly increased CD133-positive GRPs and the number of sphere formation, reflecting the self-renewal activity, of PC9 and HCC827 cells under the high concentration of gefitinib in vitro. Furthermore, Oct4-overexpressing PC9 cells (PC9-Oct4) significantly formed tumors at 1 × 10 cells/injection in NOG mice as compared to control cells. In addition, PC9-Oct4 tumors were more resistant to gefitinib treatment as compared to control cells in vivo. Finally, immunohistochemical analysis revealed that Oct4 was highly expressed in tumor specimens of EGFR-mutant NSCLC patients with acquired resistance to gefitinib. Collectively, these findings suggest that Oct4 plays a pivotal role in the maintenance of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC.
  • Hiroyuki Moriyama; Mariko Moriyama; Kiyofumi Ninomiya; Toshio Morikawa; Takao Hayakawa
    Biological & pharmaceutical bulletin (公社)日本薬学会 39 (10) 1675 - 1682 0918-6158 2016 [Refereed]
     
    Human malignant melanomas remain associated with dismal prognosis due to their resistance to apoptosis and chemotherapy. There is growing interest in plant oligostilbenoids owing to their pleiotropic biological activities, including anti-inflammatory, antioxidant, and anticancer effects. Recent studies have demonstrated that resveratrol, a well-known stilbenoid from red wine, exhibits cell cycle-disrupting and apoptosis-inducing activities on melanoma cells. The objective of our study was to evaluate the anti-melanoma effect of oligostilbenoids isolated from the bark of Shorea roxburghii. Among the isolates, four resveratrol oligomers, i.e., (-)-hopeaphenol, vaticanol B, hemsleyanol D, and (+)-α-viniferin, possessed more potent antiproliferative action than did resveratrol against SK-MEL-28 melanoma cells. Cell cycle analysis revealed that (-)-hopeaphenol, hemsleyanol D, and (+)-α-viniferin arrested cell division cycle at the G1 phase, whereas vaticanol B had little effect on the cell cycle. In addition, cell proliferation assay also revealed that (+)-α-viniferin induced DNA damage followed by induction of apoptosis in SK-MEL-28 cells, which was confirmed by an increased expression of γ-H2AX and cleaved caspase-3, respectively. The compounds vaticanol B, hemsleyanol D, and resveratrol significantly increased the expression of p21, suggesting that they are able to block cell cycle progression. Moreover, these oligostilbenoids downmodulated cylin D1 expression and extracellular signal-regulated kinase (ERK) activation. Furthermore, hemsleyanol D, (+)-α-viniferin, and resveratrol significantly decreased the expression of cyclin B1, which could also suppress cell cycle progression. The present study thus suggests that these plant oligostilbenoids are effective as therapeutic or chemopreventive agents against melanoma.
  • Mariko Moriyama; Hiroyuki Moriyama; Junki Uda; Hirokazu Kubo; Yuka Nakajima; Arisa Goto; Junji Akaki; Ikuyo Yoshida; Nobuya Matsuoka; Takao Hayakawa
    PloS one PUBLIC LIBRARY SCIENCE 11 (10) e0164799  1932-6203 2016 [Refereed]
     
    Aloe has been used as a folk medicine because it has several important therapeutic properties. These include wound and burn healing, and Aloe is now used in a variety of commercially available topical medications for wound healing and skin care. However, its effects on epidermal keratinocytes remain largely unclear. Our data indicated that both Aloe vera gel (AVG) and Cape aloe extract (CAE) significantly improved wound healing in human primary epidermal keratinocytes (HPEKs) and a human skin equivalent model. In addition, flow cytometry analysis revealed that cell surface expressions of β1-, α6-, β4-integrin, and E-cadherin increased in HPEKs treated with AVG and CAE. These increases may contribute to cell migration and wound healing. Treatment with Aloe also resulted in significant changes in cell-cycle progression and in increases in cell number. Aloe increased gene expression of differentiation markers in HPEKs, suggesting roles for AVG and CAE in the improvement of keratinocyte function. Furthermore, human skin epidermal equivalents developed from HPEKs with medium containing Aloe were thicker than control equivalents, indicating the effectiveness of Aloe on enhancing epidermal development. Based on these results, both AVG and CAE have benefits in wound healing and in treatment of rough skin.
  • Hiroyuki Moriyama; Mariko Moriyama; Haruki Isshi; Shin Ishihara; Hanayuki Okura; Akihiro Ichinose; Toshiyuki Ozawa; Akifumi Matsuyama; Takao Hayakawa
    Stem cells and development MARY ANN LIEBERT, INC 23 (18) 2211 - 24 1547-3287 2014/09 [Refereed]
     
    Human adipose tissue-derived multilineage progenitor cells (hADMPCs) are attractive for cell therapy and tissue engineering because of their multipotency and ease of isolation without serial ethical issues. However, their limited in vitro lifespan in culture systems hinders their therapeutic application. Some somatic stem cells, including hADMPCs, are known to be localized in hypoxic regions; thus, hypoxia may be beneficial for ex vivo culture of these stem cells. These cells exhibit a high level of glycolytic metabolism in the presence of high oxygen levels and further increase their glycolysis rate under hypoxia. However, the physiological role of glycolytic activation and its regulatory mechanisms are still incompletely understood. Here, we show that Notch signaling is required for glycolysis regulation under hypoxic conditions. Our results demonstrate that 5% O2 dramatically increased the glycolysis rate, improved the proliferation efficiency, prevented senescence, and maintained the multipotency of hADMPCs. Intriguingly, these effects were not mediated by hypoxia-inducible factor (HIF), but rather by the Notch signaling pathway. Five percent O2 significantly increased the level of activated Notch1 and expression of its downstream gene, HES1. Furthermore, 5% O2 markedly increased glucose consumption and lactate production of hADMPCs, which decreased back to normoxic levels on treatment with a γ-secretase inhibitor. We also found that HES1 was involved in induction of GLUT3, TPI, and PGK1 in addition to reduction of TIGAR and SCO2 expression. These results clearly suggest that Notch signaling regulates glycolysis under hypoxic conditions and, thus, likely affects the cell lifespan via glycolysis.
  • Mariko Moriyama; Hiroyuki Moriyama; Junki Uda; Akifumi Matsuyama; Masatake Osawa; Takao Hayakawa
    The Journal of investigative dermatology NATURE PUBLISHING GROUP 134 (6) 1627 - 1635 0022-202X 2014/06 [Refereed]
     
    Transcriptome analysis of the epidermis of Hes1(-/-) mouse revealed the direct relationship between Hes1 (hairy and enhancer of split-1) and BNIP3 (BCL2 and adenovirus E1B 19-kDa-interacting protein 3), a potent inducer of autophagy. Keratinocyte differentiation is going along with activation of lysosomal enzymes and organelle clearance, expecting the contribution of autophagy in this process. We found that BNIP3 was expressed in the suprabasal layer of the epidermis, where autophagosome formation is normally observed. Forced expression of BNIP3 in human primary epidermal keratinocytes (HPEKs) resulted in autophagy induction and keratinocyte differentiation, whereas knockdown of BNIP3 had the opposite effect. Intriguingly, addition of an autophagy inhibitor significantly suppressed the BNIP3-stimulated differentiation of keratinocytes, suggesting that BNIP3 plays a crucial role in keratinocyte differentiation by inducing autophagy. Furthermore, the number of dead cells increased in the human epidermal equivalent of BNIP3 knockdown keratinocytes, which suggests that BNIP3 is important for maintenance of skin epidermis. Interestingly, although UVB irradiation stimulated BNIP3 expression and cleavage of caspase3, suppression of UVB-induced BNIP3 expression led to further increase in cleaved caspase3 levels. This suggests that BNIP3 has a protective effect against UVB-induced apoptosis in keratinocytes. Overall, our data provide valuable insights into the role of BNIP3 in the differentiation and maintenance of epidermal keratinocytes.
  • Akiko Murakami; Fumiyuki Takahashi; Fariz Nurwidya; Isao Kobayashi; Kunihiko Minakata; Muneaki Hashimoto; Takeshi Nara; Motoyasu Kato; Ken Tajima; Naoko Shimada; Shin-ichiro Iwakami; Mariko Moriyama; Hiroyuki Moriyama; Fumiaki Koizumi; Kazuhisa Takahashi
    PloS one PUBLIC LIBRARY SCIENCE 9 (1) e86459  1932-6203 2014 [Refereed]
     
    Accumulating evidence indicates that a small population of cancer stem cells (CSCs) is involved in intrinsic resistance to cancer treatment. The hypoxic microenvironment is an important stem cell niche that promotes the persistence of CSCs in tumors. Our aim here was to elucidate the role of hypoxia and CSCs in the resistance to gefitinib in non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9 and HCC827, which express the EGFR exon 19 deletion mutations, were exposed to high concentration of gefitinib under normoxic or hypoxic conditions. Seven days after gefitinib exposure, a small fraction of viable cells were detected, and these were referred to as "gefitinib-resistant persisters" (GRPs). CD133, Oct4, Sox2, Nanog, CXCR4, and ALDH1A1-all genes involved in stemness-were highly expressed in GRPs in PC9 and HCC827 cells, and PC9 GRPs exhibited a high potential for tumorigenicity in vivo. The expression of insulin-like growth factor 1 (IGF1) was also upregulated and IGF1 receptor (IGF1R) was activated on GRPs. Importantly, hypoxic exposure significantly increased sphere formation, reflecting the self-renewal capability, and the population of CD133- and Oct4-positive GRPs. Additionally, hypoxia upregulated IGF1 expression through hypoxia-inducible factor 1α (HIF1α), and markedly promoted the activation of IGF1R on GRPs. Knockdown of IGF1 expression significantly reduced phosphorylated IGF1R-expressing GRPs under hypoxic conditions. Finally, inhibition of HIF1α or IGF1R by specific inhibitors significantly decreased the population of CD133- and Oct4-positive GRPs, which were increased by hypoxia in PC9 and HCC827 cells. Collectively, these findings suggest that hypoxia increased the population of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC by activating IGF1R. Targeting the IGF1R pathway may be a promising strategy for overcoming gefitinib resistance in EGFR mutation-positive NSCLC induced by lung CSCs and microenvironment factors such as tumor hypoxia.
  • Hiroyuki Moriyama; Mariko Moriyama; Kei Sawaragi; Hanayuki Okura; Akihiro Ichinose; Akifumi Matsuyama; Takao Hayakawa
    PloS one 6 8 (6) e66274  2013 [Refereed]
     
    Genetic modification of human adipose tissue-derived multilineage progenitor cells (hADMPCs) is highly valuable for their exploitation in therapeutic applications. Here, we have developed a novel single tet-off lentiviral vector platform. This vector combines (1) a modified tetracycline (tet)-response element composite promoter, (2) a multi-cistronic strategy to express an improved version of the tet-controlled transactivator and the blasticidin resistance gene under the control of a ubiquitous promoter, and (3) acceptor sites for easy recombination cloning of the gene of interest. In the present study, we used the cytomegalovirus (CMV) or the elongation factor 1 α (EF-1α) promoter as the ubiquitous promoter, and EGFP was introduced as the gene of interest. hADMPCs transduced with a lentiviral vector carrying either the CMV promoter or the EF-1α promoter were effectively selected by blasticidin without affecting their stem cell properties, and EGFP expression was strictly regulated by doxycycline (Dox) treatment in these cells. However, the single tet-off lentiviral vector carrying the EF-1α promoter provided more homogenous expression of EGFP in hADMPCs. Intriguingly, differentiated cells from these Dox-responsive cell lines constitutively expressed EGFP only in the absence of Dox. This single tet-off lentiviral vector thus provides an important tool for applied research on hADMPCs.
  • Tateki Yoshino; Hiroyuki Moriyama; Masayuki Fukushima; Noriaki Sanda
    UROLOGIA INTERNATIONALIS KARGER 90 (3) 365 - 368 0042-1138 2013 [Refereed]
     
    IgG4-related sclerosing disease is a novel clinicopathological entity characterized by fibrosis, extensive infiltration of IgG4-positive plasma cells, and serum IgG4 elevation. This disorder includes a variety of diseases, such as autoimmune pancreatitis, retroperitoneal fibrosis, sialadenitis, thyroiditis, inflammatory abdominal aneurysm, tubulointerstitial nephritis, and inflammatory pseudotumor [World J Gastroenterol 2008;14:3948-3955]. A 71-year-old man visited our hospital with the complaint of left flank pain and gross hematuria. Computed tomography (CT) revealed left hydronephrosis and a thick retroperitoneal soft tissue mass around the ureteropelvic junction, suspicious of renal pelvic cancer. Urine cytology using a urine sample from the left renal pelvis was negative. On laboratory examination, serum levels of IgG and IgG4 were found to be elevated. The patient refused tumor biopsy. Therefore, he was treated with corticosteroid therapy on the basis of a clinical diagnosis with IgG4-related retroperitoneal fibrosis. Regression of the retroperitoneal mass as well as improvement of left hydronephrosis and decrease in serum IgG4 levels were accomplished. These effects strongly suggested that the present case was an IgG4-related retroperitoneal fibrosis. However, in this instance, since we could not completely rule out malignancies by biopsy, careful follow-up was necessary with these points in mind. Copyright (C) 2012 S. Karger AG, Basel
  • Mariko Moriyama; Hiroyuki Moriyama; Ayaka Ueda; Yusuke Nishibata; Hanayuki Okura; Akihiro Ichinose; Akifumi Matsuyama; Takao Hayakawa
    BMC cell biology BIOMED CENTRAL LTD 13 21 - 21 1471-2121 2012/08 [Refereed]
     
    BACKGROUND: Adipose tissues contain populations of pluripotent mesenchymal stem cells that also secrete various cytokines and growth factors to support repair of damaged tissues. In this study, we examined the role of oxidative stress on human adipose-derived multilineage progenitor cells (hADMPCs) in neurite outgrowth in cells of the rat pheochromocytoma cell line (PC12). RESULTS: We found that glutathione depletion in hADMPCs, caused by treatment with buthionine sulfoximine (BSO), resulted in the promotion of neurite outgrowth in PC12 cells through upregulation of bone morphogenetic protein 2 (BMP2) and fibroblast growth factor 2 (FGF2) transcription in, and secretion from, hADMPCs. Addition of N-acetylcysteine, a precursor of the intracellular antioxidant glutathione, suppressed the BSO-mediated upregulation of BMP2 and FGF2. Moreover, BSO treatment caused phosphorylation of p38 MAPK in hADMPCs. Inhibition of p38 MAPK was sufficient to suppress BMP2 and FGF2 expression, while this expression was significantly upregulated by overexpression of a constitutively active form of MKK6, which is an upstream molecule from p38 MAPK. CONCLUSIONS: Our results clearly suggest that glutathione depletion, followed by accumulation of reactive oxygen species, stimulates the activation of p38 MAPK and subsequent expression of BMP2 and FGF2 in hADMPCs. Thus, transplantation of hADMPCs into neurodegenerative lesions such as stroke and Parkinson's disease, in which the transplanted hADMPCs are exposed to oxidative stress, can be the basis for simple and safe therapies.
  • Hanayuki Okura; Ayami Saga; Mayumi Soeda; Jyunko Tani; Mariko Moriyama; Hiroyuki Moriyama; Shizuya Yamashita; Akihiro Ichinose; Shinya Tahara; Takao Hayakawa; Akifumi Matsuyama
    CIRCULATION LIPPINCOTT WILLIAMS & WILKINS 124 (21) 0009-7322 2011/11 [Refereed]
  • Hanayuki Okura; Ayami Saga; Mayumi Soeda; Jyunko Tani; Mariko Moriyama; Hiroyuki Moriyama; Sihizuya Yamashita; Akihiro Ichinose; Shinya Tahara; Takao Hayakawa; Akifumi Matsuyama
    CIRCULATION LIPPINCOTT WILLIAMS & WILKINS 124 (21) 0009-7322 2011/11 [Refereed]
  • Ayami Saga; Hanayuki Okura; Mayumi Soeda; Junko Tani; Yuichi Fumimoto; Hiroshi Komoda; Mariko Moriyama; Hiroyuki Moriyama; Shizuya Yamashita; Akihiro Ichinose; Takashi Daimon; Takao Hayakawa; Akifumi Matsuyama
    Biochemical and biophysical research communications 1 412 (1) 50 - 4 0006-291X 2011/08 [Refereed]
     
    Familial hypercholesterolemia (FH) is an autosomal codominant disease characterized by high concentrations of proatherogenic lipoproteins secondary to deficiency in low-density lipoprotein (LDL) receptor. We reported recently the use of in situ stem cell therapy of human adipose tissue-derived multilineage progenitor cells (hADMPCs) in lowering serum total cholesterol in the homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of homozygous FH. Here we demonstrate that pravastatin, an HMG-CoA reductase inhibitor, augmented the cholesterol-lowering effect of transplanted hADMPCs and enhanced LDL clearance in homozygous WHHL rabbit. The results suggest the potential beneficial effects of in situ stem cell therapy in concert with appropriately selected pharmaceutical agents, in regenerative medicine.
  • Hanayuki Okura; Ayami Saga; Yuichi Fumimoto; Mayumi Soeda; Mariko Moriyama; Hiroyuki Moriyama; Koji Nagai; Chun-Man Lee; Shizuya Yamashita; Akihiro Ichinose; Takao Hayakawa; Akifumi Matsuyama
    Tissue engineering. Part C, Methods MARY ANN LIEBERT, INC 17 (2) 145 - 54 1937-3384 2011/02 [Refereed]
     
    Familial hypercholesterolemia (FH) is an autosomal codominant disease characterized by high concentrations of proatherogenic lipoproteins and premature atherosclerosis secondary to low-density lipoprotein (LDL) receptor deficiency. We examined a novel cell therapy strategy for the treatment of FH in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for homozygous FH. We delivered human adipose tissue-derived multilineage progenitor cells (hADMPCs) via portal vein and followed by immunosuppressive regimen to avoid xenogenic rejection. Transplantation of hADMPCs resulted in significant reductions in total cholesterol, and the reductions were observed within 4 weeks and maintained for 12 weeks. (125)I-LDL turnover study showed that the rate of LDL clearance was significantly higher in the WHHL rabbits with transplanted hADMPCs than those without transplanted. After transplantation hADMPCs were localized in the portal triad, subsequently integrated into the hepatic parenchyma. The integrated cells expressed human albumin, human alpha-1-antitrypsin, human Factor IX, human LDL receptors, and human bile salt export pump, indicating that the transplanted hADMPCs resided, survived, and showed hepatocytic differentiation in vivo and lowered serum cholesterol in the WHHL rabbits. These results suggested that hADMPC transplantation could correct the metabolic defects and be a novel therapy for inherited liver diseases.
  • Mariko Moriyama; Andre-Dante Durham; Hiroyuki Moriyama; Kiyotaka Hasegawa; Shin-Ichi Nishikawa; Freddy Radtke; Masatake Osawa
    DEVELOPMENTAL CELL CELL PRESS 14 (4) 594 - 604 1534-5807 2008/04 [Refereed]
     
    Recent studies have shown that Notch signaling plays an important role in epidermal development, but the underlying molecular mechanisms remain unclear. Here, by integrating loss- and gain -of-function studies of Notch receptors and Hes1, we describe molecular information about the role of Notch signaling in epidermal development. We show that Notch signaling determines spinous cell fate and induces terminal differentiation by a mechanism independent of Hes1, but Hes1 is required for maintenance of the immature state of spinous cells. Notch signaling induces Ascl2 expression to promote terminal differentiation, while simultaneously repressing Ascl2 through Hes1 to inhibit premature terminal differentiation. Despite the critical role of Hes1 in epidermal development, Hes1 null epidermis transplanted to adult mice showed no obvious defects, suggesting that this role of Hes1 may be restricted to developmental stages. Overall, we conclude that Notch signaling orchestrates the balance between differentiation and immature programs in suprabasal cells during epidermal development.
  • Hiroyuki Moriyama; Shin Yonehara
    Immunology letters ELSEVIER SCIENCE BV 109 (1) 36 - 46 0165-2478 2007/03 [Refereed]
     
    Cross-linking of BCR rapidly induces protection of B cells from Fas-mediated apoptosis, which has been assumed one of the important survival mechanisms of B cells during antigen stimulation. In the mouse B cell line A20, which is sensitive to Fas-mediated apoptosis, stimulation of BCR inhibited apoptosis induced via Fas upstream of caspase-8 activation with an associated rapid increase in the expression of both short and long forms of cellular caspase-8/FLICE-inhibitory protein (c-FLIP). The c-FLIP competitively inhibited the recruitment of caspase-8 to the death-inducing signaling complex (DISC), which took as long as 3h to form after the stimulation of Fas in A20 cells. Knockdown of c-FLIP by a short hairpin RNA-expressing method rendered BCR-stimulated A20 cells sensitive to Fas-mediated apoptosis. The BCR-induced rapid expression of c-FLIP was not affected by inactivation of NF-kappaB, but was inhibited by either treatment with a PI3K inhibitor, LY294002, or expression of a dominant negative PI3K p85 subunit, both of which suppressed phosphorylation of Akt and sensitized BCR-stimulated A20 cells to Fas-mediated apoptosis. Overexpression of constitutively active Akt was shown not only to up-regulate c-FLIP expression but also to render A20 cells resistant to Fas-mediated apoptosis. Moreover, treatment with LY294002 also suppressed BCR-induced up-regulation of c-FLIP expression in spleen B cells. Taken together, BCR-stimulation was shown to rapidly trigger a survival signal against simultaneously or ongoingly stimulated Fas-mediated apoptosis by promoting a PI3K/Akt signaling pathway-mediated up-regulation of c-FLIP expression.
  • B Bikandou; J Takehisa; I Mboudjeka; E Ido; T Kuwata; Y Miyazaki; H Moriyama; Y Harada; Y Taniguchi; H Ichimura; M Ikeda; P J Ndolo; M Y Nzoukoudi; R M'Vouenze; M M'Pandi; H J Parra; P M'Pelé; M Hayami
    AIDS research and human retroviruses 16 (7) 613 - 9 0889-2229 2000/05 [Refereed]
     
    To assess the molecular epidemiology of HIV-1 in Republic of Congo (Congo), we investigated 29 HIV-1s obtained from 82 Congolese AIDS and ARC patients in 1996 and 1997. Part of the env region including the V3 loop was phylogenetically analyzed. The genotypes observed were varied: of 29 specimens, 12 (41 %) were subtype A, 1 (3%) was subtype D, 6 (21%) were subtype G, 6 (21%) were subtype H, 2 (7%) were subtype J, and 2 (7%) could not be classified as any known subtypes (U, unclassified). The heterogeneous profile of HIV-1 infection was different from the profiles of neighboring Central African countries. These data show that subtypes G and H as well as subtype A were circulating with high prevalence. The fact that new genetic subtypes (J and U) are circulating indicates a need for a greater surveillance for these subtypes both in Congo as well as in other parts of the world.
  • J Takehisa; L Zekeng; E Ido; I Mboudjeka; H Moriyama; T Miura; M Yamashita; L G Gürtler; M Hayami; L Kaptué
    Virology 245 (1) 1 - 10 0042-6822 1998/05 [Refereed]
     
    In order to assess the incidence of HIV mixed infection as well as to clarify the molecular epidemiology of HIV in central Africa, we investigated 43 HIVs obtained from 211 Cameroonian AC, ARC, and AIDS patients in 1994 and 1995. Part of the pol region and part of the env region were phylogenetically analyzed. The genotypes observed were varied: of 43 specimens, 28 (65%) were subtype A, 1 (2%) was subtype B, 2 (5%) were subtype D, 3 (7%) were subtype F, and 2 (5%) were group O. Of the remaining 7 specimens, 3 were mixed infections with HIV-1 subtypes A and C, HIV-1 subtypes C and F, and HIV-2 subtype A and HIV-1 subtype A; 1 was a mixed infection with HIV-1 subtypes A and D and the highly divergent group O (triple infection); another 3 appeared to consist of mosaic genomes (A/G, A/E, and B/A recombinant). These data show that various types of mixed infection, such as between different subtypes of HIV-1 group M, between HIV-1 and HIV-2, and even between HIV-1 groups O and M, were confirmed at a rather high frequency (approximately 10%). The mixed infection is particularly significant where there is a greater variety of HIV-1 subtypes circulating, since it results in new genetic diversity generated by intersubtype recombination.
  • T Igarashi; T Kuwata; H Yamamoto; H Moriyama; M Ui; Y Miyazaki; M Hayami
    Microbiology and immunology 42 (1) 71 - 4 0385-5600 1998 [Refereed]
     
    Two SHIVs with two or three genes deleted (SHIV-drn and SHIV-dxrn) were constructed. The inoculation of monkeys with SHIV-drn resulted in short-term viremia, but inoculation with SHIV-dxrn did not. At 68 weeks post-inoculation, the monkeys were reinoculated with a 100-fold higher dose of each SHIV, but none showed viremia. Killer cell activities against HIV-1 Env were detected in the SHIV-drn- and SHIV-dxrn-inoculated monkeys. Cross-reactive killer activity against HIV-1 Gag and SIVmac Gag was observed in one monkey. Antibodies were not detected in the SHIV-dxrn-inoculated monkeys, but the SHIV-drn-inoculated monkeys showed an anamnestic antibody reaction. These data indicate that SHIV-drn is infectious to and immuno-inducible in macaques but SHIV-dxrn is not.

Books etc

  • バイオロジクスの開発と品質・安全性確保（上巻）
    森山博由; 他; 早川堯夫 (Joint editorタンパク質性バイオ医薬品の開発と品質・安全性確保)（株）エル・アイ・シー 2018/09
  • 森山博由; 他; 早川堯夫 (Joint editorバイオシミラーの開発と品質・安全性確保体 / 再生医療等製品の開発と品質・安全性確保 / 性幹細胞, 間葉系幹細胞の特性解析, 品質・安全性確保)エル・アイ・シー 2018/09 9784900487567

MISC

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Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2021/04 -2024/03 
    Author : 森山 博由
     
    本研究は、真の脂肪組織由来間葉系間質幹細胞(hASC)の実像に迫るべく、高解像度のシングルセルレベル解析ならびに性状解析を実施し、未だ未同定のhASCに迫る科学的な成果の探究を目的とする。また、その成果を再生医療に資するhASCの提供（質と量を担保できる橋渡し）としての実用化研究へと連結することも終局目標に据えている。そのため当該年度は、(1) トランスクリプトームレベルでの発現解析と候補遺伝子の峻別を実施し、特徴的な遺伝子発現集団とその遺伝子群のマトランスクリプトームルチオミクス解析から、少なくとも6~7つの亜集団とその遷移または独立関係、ならびに、マーカー候補分子や特異的分化能を有すると思しき遺伝子(群)のヒエラルキーを見出した。また、(2) タンパク質レベルでの候補遺伝子のバリデーション（検証）を行い、(1)で選出した特異的分化能を有すると思しき遺伝子(群)の一部につき、間葉系終末細胞群もしくは外胚葉系終末細胞群への特異的な分化能との関わりが在る事を見出した。さらに、一部の終末細胞については、組織特異的な分化誘導のもと、その機能性についての解析を行い、論文化をすすめた。さらに高度な細胞性状解析を行うため、(3)遺伝子導入系の精査と細胞性状解析のコントロール細胞系列の選定を行い、本解析に至適な、よりhASCの形質維持や分化誘導を制御し易いと思しき遺伝子導入系、ならびに従前に定義されているいわゆるhASを安定した状態で維持できるような培養系の向上、同義に高度な性状解析のためのコントロール細胞(郡)の確立を行った。このよに、総じて本研究は各年度計画を達成するよう、おもだった予備的な結果を紡げていることから、有意義な研究が展開されているものと思われる。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2017/04 -2020/03 
    Author : Hiroyuki Moriyama
     
    We identified a group of key genes responsible (a master regulators) for the hypoxia response in adipose-derived mesenchymal stromal/stem cells, and were selected characteristic marker expressing on cell surface. By further segregation of these cell subgroups, we found that they tend to differentiate into various terminal differentiated cells especially belonging to the mesenchymal lineage. This led to the isolation of a subpopulation of Hx-hASCs that are proficient in adipocyte differentiation using the master regulator as an indicator, and the narrowing down to a sharpening of the subpopulation for the unique hASCs. In addition, we found that the synergistic effect of fibroblasts on the maintenance of epithelial cells, such as keratinocytes, and the qualitative and quantitative balance between fibroblasts and the adipose-derived mesenchymal stem cell subgroups affect the turnover of the dermal layer, albeit at a preliminary level in the basic study of the artificial skin 3D model.
  • 新規ヒト脂肪組織間葉系幹細胞を用いた糖代謝制御機構の解明と高品質な脂肪細胞の創製
    文部科学省：科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2017/04 -2020/03 
    Author : 森山博由
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : MORIYAMA Mariko; MORIYAMA Hiroyuki
     
    Previously, we found that BNIP3 plays a crucial role in keratinocytes differentiation by inducing autophagy. Furthermore, BNIP3 has a protective effect against UVB-induced apoptosis in keratinocytes. In this study, we found that the accumulation of reactive oxygen species (ROS) and following activation of ERK/JNK MAP kinase by UVB irradiation was sufficient to trigger the upregulation of BNIP3 expression. Moreover, BNIP3 was required for the degradation of dysfunctional mitochondria upon UVB irradiation. These data clearly indicated that BNIP3-induced autophagy, which occurs via UVB-generated ROS-mediated JNK and ERK MAPK activation, has a crucial role in the protection of the skin epidermis against UVB irradiation.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014 -2016 
    Author : MORIYAMA Hiroyuki; MORIYAMA Mariko
     
    Human adipose tissue-derived multilineage progenitor cells (hADMPCs) are attractive for cell therapy and tissue engineering because of their multipotency and ease of isolation without serial ethical issues. Here, we show that Notch signaling is required for glycolysis regulation under hypoxic conditions. Our results demonstrate that 5% O2 dramatically increased the glycolysis rate, improved the proliferation efficiency, prevented senescence, and maintained the multi potency of hADMPCs. Hypoxia significantly increased the level of activated Notch1 and expression of its downstream gene, HES1. Furthermore, Hypoxia markedly increased glucose consumption and lactate production, which decreased back to normoxic levels on treatment with a g-secretase inhibitor. We also found that HES1 was involved in induction of GLUT3, TPI, and PGK1 in addition to reduction of TIGAR and SCO2 expression. These results clearly suggest that Notch signaling regulates glycolysis under hypoxic conditions.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2012 -2013 
    Author : MORIYAMA Hiroyuki
     
    In this study, we examined the role of oxidative stress on human adipose-derived multilineage progenitor cells (hADMPCs) in neurite outgrowth in PC12. We found that glutathione depletion, followed by accumulation of reactive oxygen species, stimulates the expression of BMP2 and FGF2 in hADMPCs. Addition of N-acetylcysteine, a precursor of the intracellular antioxidant glutathione, suppressed the BSO-mediated upregulation of BMP2 and FGF2. Moreover, BSO treatment caused phosphorylation of p38 MAPK in hADMPCs. Inhibition of p38 MAPK was sufficient to suppress BMP2 and FGF2 expression, while this expression was significantly upregulated by overexpression of a constitutively active form of MKK6, which is an upstream molecule from p38 MAPK. Thus, transplantation of hADMPCs into neurodegenerative lesions such as stroke and Parkinson's disease, in which the transplanted hADMPCs are exposed to oxidative stress, can be the basis for simple and safe therapies.

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