Faculty Profiles - ITO Akira

Papers - ITO Akira

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Intramyocardial Transplantation ofHuman iPS Cell–Derived CardiacSpheroids Improves Cardiac Function inHeart Failure Animals. Reviewed

JACC: Basic to Translational Science Vol. 36 ( 4 ) page： 101 - 108 2021

Heat dose based large tumor treatment with multiple site injections of heat-generating nanoparticles dispersible within tumor tissue Reviewed

2. Tomio Morino, Akira Ito, Toshiki Etani, Taku Naiki, Noriyasu Kawai, Takahiro Yasui

Thermal Medicine Vol. 36 ( 4 ) page： 104 - 108 2020.12

Heat Dose Based Large Tumor Treatment with Multiple Site Injections of Heat-generating Nanoparticles Dispersible within Tumor Tissue

MORINO TOMIO, ITO AKIRA, ETANI TOSHIKI, NAIKI TAKU, KAWAI NORIYASU, YASUI TAKAHIRO

Thermal Medicine Vol. 36 ( 4 ) page： 101 - 108 2020.12

Language：English Publisher：Japanese Society for Thermal Medicine

Solid cancer therapy based on necrosis induction with heat-generating nanoparticles has been developed in Japan. Heat was induced from intratumorally injected magnetite cationic lipid composite particles (MCL particles) by alternating magnetic field irradiations to kill cancer cells nearby located. In our previous report we have showed importance of heat dose index in vivo (J/cm3 tumor volume) for tumor regression when 45 mg MCL particles were injected at a single site of 1.36 cm3 tumor. Purpose of this study is to show rationale and utility of multiple site injections of MCL particles for treatment of large tumors more than 1.36 cm3.Rat mammary tumors were induced by 7,12-dimethylbenz［a］anthracene (DMBA) and tumors in range of 2.19 ～ 3.81 cm3 were applied to treatment experiment. Treatment condition was designed to reproduce the heat generation condition of the 1.36 cm3 tumor treatment at every multiple injection site in rat mammary tumors. Tumor volume divided by number of injection sites (cm3/site) was set to close to 1.36 cm3/site and 45 mg MCL particles were administered at multiple sites to keep even spaces among injection sites. Three irradiation conditions were set to give close heat dose in vivo (J/cm3) of the 1.36 cm3 tumor treatment. Treatment under designed conditions resulted in complete regression of rat tumors at 21 days after the treatment, showing theoretical validity of design procedures for the multiple site injections. Novel concept of necrosed tumor volume from an injection site (cm3/site) and its actual value under a standard injection condition of 45 mg-MCL/site were described and its use in clinic was discussed.

DOI： 10.3191/thermalmed.36.101

CiNii Research

ハイパーサーミアの新展開 -基礎医学・臨床応用に関する最近の進歩- Reviewed

近藤隆、鈴木文男、水上達治、斎藤淳一、河合憲康、井藤　彰

放射線生物研究 Vol. 55 ( 3 ) page： 210 - 228 2020.9

Magnetic heating of nanoparticles as a scalable cryopreservation technology for human induced pluripotent stem cells

Ito Akira, Yoshioka Kantaro, Masumoto Shinya, Sato Keiichiro, Hatae Yuki, Nakai Tomoki, Yamazaki Takashi, Takahashi Masazumi, Tanoue Shota, Horie Masanobu

SCIENTIFIC REPORTS Vol. 10 ( 1 ) 2020.8

Heat Dose Index in vivo for Cancer Therapy Using Heat-generating Nanoparticles Named Magnetite Cationic Liposomes and Alternating Magnetic Field Irradiator

MORINO TOMIO, TANOUE SHOTA, MIYATA SHUICHIRO, HIRAYAMA KOTARO, ITO AKIRA, ETANI TOSHIKI, NAIKI TAKU, KAWAI NORIYASU, YASUI TAKAHIRO

Thermal Medicine Vol. 36 ( 2 ) page： 47 - 58 2020.7

Language：English Publisher：Japanese Society for Thermal Medicine

Cancer clinical research using heat-generating nanoparticles named magnetite cationic liposomes (MCL) and alternating magnetic field (AMF) irradiator has been conducted. Heat generation from intratumorally injected MCL particles was triggered by AMF irradiation to kill cancer cells nearby located. Tumor temperature was monitored as index to control treatment condition but efficacy was variable from complete regression to ineffective. In order to improve efficacy, we have proposed novel index of heat dose in vivo (J/cm3 tumor volume). Purpose of this study was to reveal actual heat dose in vivo and discuss its utility as index.In order to enable to estimate heat dose, heat generation activity of MCL particles (J/g-MCL・min) was measured under various AMF irradiation conditions by changing output power (kW) and distance from irradiation surface (mm). Treatment condition for complete regression of animal tumors with 7 mm diameter was reproduced and heat dose in vivo (J/cm3) was calculated by multiplying heat generation activity (J/g-MCL・min) with MCL dosage (g-MCL/cm3) and irradiation time (min). Heat dose for tumor regression was revealed around 700-850 J/cm3 in every thrice AMF irradiations of a course. Since temperature-based treatments of large tumors were reported to fall into insufficiency, revealed heat dose was applied to design treatment condition of large tumor with 13-16 mm diameter, and complete regression was achieved by a course treatment. MCL dosage of temperature-based condition was found far lower than that of heat dose. Low MCL dosages (g-MCL/cm3) would cause shortage of heat dose (J/cm3) and insufficient anticancer activity, although tumor temperature could be raised by heat transfer to monitoring sites. These results showed utility of heat dose in vivo as index to ensure clinical efficacy and concomitantly to make useless invasive probe for temperature monitoring. Procedure to design treatment condition and required performance of AMF irradiator were described.

DOI： 10.3191/thermalmed.36.47

CiNii Research

若手化学工学者としての私の履歴書 Invited Reviewed

井藤　彰

学術の動向 Vol. 25 ( 7 ) page： 98 - 102 2020.7

A Curriculum Vitae of Mine as a Chemical Engineer

ITO Akira

TRENDS IN THE SCIENCES Vol. 25 ( 7 ) page： 7_98 - 7_102 2020.7

Heat dose index in vivo for cancer therapy using heat-generating nanoparticles named magnetite cationic liposomes and alternating magnetic field irradiator Reviewed

Tomio Morino, Shota Tanoue, Shuichiro Miyata, Kotaro Hirayama, Akira Ito, Toshiki Etani, Taku Naiki, Noriyasu Kawai, Takahiro Yasui

Vol. 36 ( 2 ) page： 47 - 58 2020.7

Novel neuromuscular junction model in 2D and 3D myotubes co-cultured with induced pluripotent stem cell-derived motor neurons. Reviewed

Kantaro Yoshioka, Akira Ito, Yoshinori Kawabe, Masamichi Kamihira

Journal of bioscience and bioengineering Vol. 129 ( 4 ) page： 486 - 493 2020.4

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

Motor neurons differentiated from induced pluripotent stem (iPS) cells have attracted attention for use in the construction of drug screening systems for neuronal diseases, such as amyotrophic lateral sclerosis. However, conventional drug screening systems using 2-dimensional (2D) cultures of iPS cell-derived motor neurons often evaluate the cell survival rate, morphological changes in the cells and/or gene expression analysis, and these parameters do not always reflect the actual functions of motor neurons, i.e., the induction of muscle contractions. In the present study, we developed a neuromuscular junction model comprising motor neurons and myotubes, which were differentiated from iPS cells and C2C12 myoblasts, respectively. Using this model, the contractile activity and force generation of the myotubes via the neuromuscular junction were successfully measured in both two- and three-dimensional (3D) cell culture systems. The results suggested that this neuromuscular junction model can be used to construct a drug candidate screening system for neuronal diseases.

DOI： 10.1016/j.jbiosc.2019.10.004

Web of Science

PubMed

Targeted knock-in into the OVA locus of chicken cells using CRISPR/Cas9 system with homology-independent targeted integration. Reviewed

Ming Shi, Yoshinori Kawabe, Akira Ito, Masamichi Kamihira

Journal of bioscience and bioengineering Vol. 129 ( 3 ) page： 363 - 370 2020.3

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

It is anticipated that transgenic avian species will be used as living bioreactors for the production of biopharmaceutical proteins. Precise tissue-specific expression of exogenous genes is a major challenge for the development of avian bioreactors. No robust vector is currently available for highly efficient and specific expression. In recent years, genome-editing techniques such as the CRISPR/Cas9 system have emerged as efficient and user-friendly genetic modification tools. Here, to apply the CRISPR/Cas9 system for the development of transgenic chickens, guide RNA sequences (gRNAs) of the CRISPR/Cas9 system for the ovalbumin (OVA) locus were evaluated for the oviduct-specific expression of exogenous genes. An EGFP gene expression cassette was introduced into the OVA locus of chicken DF-1 and embryonic fibroblasts using the CRISPR/Cas9 system mediated by homology-independent targeted integration. For the knock-in cells, EGFP expression was successfully induced by activation of the endogenous OVA promoter using the dCas9-VPR transactivation system. The combination of gRNAs designed around the OVA TATA box was important to induce endogenous OVA gene expression with high efficiency. These methods provide a useful tool for studies on the creation of transgenic chicken bioreactors and the activation of tissue-specific promoters.

DOI： 10.1016/j.jbiosc.2019.09.011

Web of Science

PubMed

Medium temperature independent cytotoxicity of cell-adhesive heat-generating nanoparticles named magnetite cationic liposomes and its therapeutic use Reviewed

Tomio Morino, Hiroshi Takase, Toshiki Etani, Taku Naiki, Noriyasu Kawai, Akira Ito, Takahiro Yasui

Thermal Medicine Vol. 36 ( 1 ) page： 25 - 34 2020.3

Cre-Mediated Transgene Integration in Chinese Hamster Ovary Cells Using Minicircle DNA Vectors. Reviewed International journal

Wang X, Kawabe Y, Hada T, Ito A, Kamihira M

Biotechnology journal Vol. 13 ( 7 ) page： e1800063 2018.7

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

Bacterial backbone sequences of conventional plasmid vectors have been reported to exhibit negative effects on transgene expression in mammalian cells, such as cytotoxicity and gene silencing. Minicircle DNA vectors can be employed to overcome these issues and to improve the transfection efficiency because of their smaller size. In this study, transgenes are integrated into the hypoxanthine phosphoribosyltransferase (hprt) locus of Chinese hamster ovary (CHO) cells by the Cre-loxP system using minicircle DNA vectors as transgene donors. The targeted transgene integration efficiency is improved 2-3-fold (≈1.4%) using minicircle DNA vectors compared with conventional plasmid vectors. Moreover, clones with expected structures after transgene integration are obtained with a high frequency. When a transgene together with bacterial sequences derived from a plasmid vector is integrated into the hprt locus, the cell growth rate and antibody titer decrease. These results indicate that minicircle DNA vectors are more suitable than conventional plasmid vectors for transgene delivery in recombinant protein production using CHO cells.

DOI： 10.1002/biot.201800063

PubMed

Targeted knock-in of an scFv-Fc antibody gene into the hprt locus of Chinese hamster ovary cells using CRISPR/Cas9 and CRIS-PITCh systems Reviewed

Yoshinori Kawabe, Shinya Komatsu, Shodai Komatsu, Mai Murakami, Akira Ito, Tetsushi Sakuma, Takahiro Nakamura, Takashi Yamamoto, Masamichi Kamihira

Journal of Bioscience and Bioengineering Vol. 125 ( 5 ) page： 599 - 605 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

Chinese hamster ovary (CHO) cells have been used as host cells for the production of pharmaceutical proteins. For the high and stable production of target proteins, the transgene should be integrated into a suitable genomic locus of host cells. Here, we generated knock-in CHO cells, in which transgene cassettes without a vector backbone sequence were integrated into the hprt locus of the CHO genome using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and CRISPR-mediated precise integration into target chromosome (CRIS-PITCh) systems. We investigated the efficiency of targeted knock-in of transgenes using these systems. As a practical example, we generated knock-in CHO cells producing an scFv-Fc antibody using the CRIS-PITCh system mediated by microhomology sequences for targeting. We found that the CRIS-PITCh system can facilitate targeted knock-in for CHO cell engineering.

DOI： 10.1016/j.jbiosc.2017.12.003

Scopus

PubMed

Characterization of genetically engineered mouse hepatoma cells with inducible liver functions by overexpression of liver-enriched transcription factors Reviewed

Hideaki Yamamoto, Jane Marie Tonello, Takanori Sambuichi, Yoshinori Kawabe, Akira Ito, Masamichi Kamihira

Journal of Bioscience and Bioengineering Vol. 125 ( 1 ) page： 131 - 139 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

New cell sources for the research and therapy of organ failure could significantly alleviate the shortage of donor livers that are available to patients who suffer from liver disease. Liver carcinoma derived cells, or hepatoma cells, are the ideal cells for developing bioartificial liver systems. Such cancerous liver cells are easy to prepare in large quantities and can be maintained over long periods under standard culture conditions, unlike primary hepatocytes. However, hepatoma cells possess only a fraction of the functions of primary hepatocytes. In a previous study, by transducing cells with liver-enriched transcription factors that could be inducibly overexpressed—hepatocyte nuclear factor (HNF)1α, HNF1β, HNF3β [FOXA2], HNF4α, HNF6, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ and C/EBPγ—we created mouse hepatoma cells with high liver-specific gene expression called the Hepa/8F5 cell line. In the present study, we performed functional and genetic analyses to characterize the Hepa/8F5 cell line. Further, in three-dimensional cultures, the function of these cells improved significantly compared to parental cells. Ultimately, these cells might become a new resource that can be used in basic and applied hepatic research.

DOI： 10.1016/j.jbiosc.2017.07.011

Scopus

PubMed

温熱誘導型遺伝子発現システムの開発と応用 Invited Reviewed

井藤　彰

放射線生物研究 Vol. 53 ( 2 ) page： 104-114 2018

ハイパーサーミアに伴う免疫賦活のメカニズム Invited Reviewed

井藤彰

放射線生物研究 Vol. 53 ( 2 ) page： 104-114 2018

Three-dimensional culture of a genetically modified hepatoma cell line using macroporous gelatin beads Reviewed

Jane Marie Tonello, Saori Kawashima, Kazuki Sato, Yoshinori Kawabe, Akira Ito, Masamichi Kamihira

CYTOTECHNOLOGY Vol. 69 ( 6 ) page： 925 - 931 2017.12

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

Hepatoma cells are a candidate cell source for bio-artificial livers. However, they exhibit reduced liver functions compared with primary hepatocytes. In our previous study, genetically engineered mouse hepatoma cells were created by transduction with vectors mediating inducible overexpression of eight liver-enriched transcription factors. Upon the induction of the liver-enriched transcription factors transduced, the cells expressed both phenotypic and genotypic liver functions at high levels. In the present study, we performed three-dimensional culture of these cells using macroporous gelatin beads. When immobilized on the macroporous gelatin beads, these cells exhibited further enhancement in liver functionality, including increased albumin secretion, ammonia removal and cytochrome P450 activity. The levels of these functions were significantly enhanced compared to monolayer culture. The method is simple and scalable, and provides highly functional cells that can be used in basic and applied fields of hepatic research.

DOI： 10.1007/s10616-017-0117-0

Web of Science

PubMed

Accumulative scFv-Fc antibody gene integration into the &IThprt&IT chromosomal locus of Chinese hamster ovary cells Reviewed

Xue Wang, Yoshinori Kawabe, Risa Kato, Takeshi Hada, Akira Ito, Yoshimasa Yamana, Masako Kondo, Masamichi Kamihira

JOURNAL OF BIOSCIENCE AND BIOENGINEERING Vol. 124 ( 5 ) page： 583 - 590 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SOC BIOSCIENCE BIOENGINEERING JAPAN

We have previously developed an accumulative site-specific gene integration system (AGIS) using Cre-recombinase and mutated loxP sites. AGIS enables repeated transgene integration into a predetermined chromosomal site in mammalian cells. However, the process of establishing cells with multiple integrated copies of the transgene is still time-consuming. In the present study, we describe an improved version of AGIS that facilitates and accelerates the establishment of high-producer Chinese hamster ovary (CHO) cells. Two donor vectors were simultaneously introduced into the cells in a single transfection. Cells with successfully targeted transgene integration were screened based on a change in the color of the reporter fluorescent protein that they express. Repeated rounds of integration allowed the transgene copy number to be increased. As a model, an scFv-Fc antibody gene was integrated into the hprt locus of the CHO cell genome. After three rounds of integration, a high-producer CHO cell clone with six copies of the scFv-Fc gene was successfully established. scFv-Fc productivity was approximately four-fold greater than a control cell line harboring a single copy of the transgene. This newly designed AGIS procedure should facilitate the development of producer cells suitable for biopharmaceutical protein production. (C) 2017, The Society for Biotechnology, Japan. All rights reserved.

DOI： 10.1016/j.jbiosc.2017.05.017

Web of Science

PubMed

Hypoxia-responsive transgene expression system using RTP801 promoter and synthetic transactivator fused with oxygen-dependent degradation domain Reviewed

Akihiko Ono, Akira Ito, Tomonaga Sato, Masaki Yamaguchi, Taiga Suzuki, Yoshinori Kawabe, Masamichi Kamihira

JOURNAL OF BIOSCIENCE AND BIOENGINEERING Vol. 124 ( 1 ) page： 115 - 124 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SOC BIOSCIENCE BIOENGINEERING JAPAN

Precise control of gene expression using an artificial gene circuit is a major challenge in the application of synthetic biology. Here, we designed a hypoxia-responsive transgene expression system by combining a hypoxia-inducible RTP801 promoter and a tetracycline-responsive transactivator fused with an oxygen-dependent degradation domain (TA-ODD). The reporter gene expression was highly induced by hypoxia when a transactivator-expression plasmid, pRTP801/TA-ODD, harboring a TA-ODD gene driven by the RTP801 promoter, was cotransfected with a reporter plasmid, pTRE/EGFP, harboring an EGFP gene controlled under the transactivator-responsive promoter. A stable cell line into which the expression units RTP801/TA-ODD and THE/EGFP had been introduced responded to hypoxia and expressed the reporter gene in an oxygen-concentration-dependent manner. Moreover, the cells demonstrated potential as sensors to detect hypoxic conditions in a three-dimensional tissue culture in vitro. These results indicate that the hypoxia-responsive transgene expression system is useful for constructing cell-based hypoxia detection systems. (C) 2017, The Society for Biotechnology, Japan. All rights reserved.

DOI： 10.1016/j.jbiosc.2017.02.012

Web of Science

PubMed

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Papers - ITO Akira