Papers - IWANO satoshi
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Combined Therapy Targeting MET and Pro-HGF Activation Shows Significant Therapeutic Effect Against Liver Metastasis of CRPC.
Kimura S, Iwano S, Akioka T, Kuchimaru T, Kawaguchi M, Fukushima T, Sato Y, Kataoka H, Kamoto T, Mukai S, Sawada A
International journal of molecular sciences 26 ( 5 ) 2025.3
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.3390/ijms26052308
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Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species. International journal
Natsuko Ota, Takashi Nishida, Daron M Standley, Aalaa Alrahman Sherif, Satoshi Iwano, Dendi Krisna Nugraha, Toshiya Ueno, Yasuhiko Horiguchi
Microbiology and immunology 69 ( 3 ) 133 - 147 2025.3
Language：English Publishing type：Research paper (scientific journal)
The Gram-negative bacteria Bordetella pertussis, B. parapertussis, and B. bronchiseptica cause respiratory diseases in various mammals. They share the BvgAS two-component system, which regulates the phenotypic conversion between the virulent Bvg+ and avirulent Bvg- phases. In the BvgAS system, the sensor kinase BvgS senses environmental cues and transduces a phosphorelay signal to the response regulator BvgA, which leads to the expression of Bvg+ phase-specific genes, including virulence factor genes. Bacteria grown at 37°C exhibit the Bvg+ phenotype. In contrast, at lower than 26°C or in the presence of modulators, such as MgSO4 and nicotinic acid, the BvgAS system is inactivated, leading bacteria to the avirulent Bvg- phase. Therefore, effective modulators are expected to provide a therapeutic measure for Bordetella infection; however, no such modulators are currently available, and the mechanism by which modulators inactivate the BvgAS system is poorly understood. In the present study, we identified lonidamine as a novel modulator after screening an FDA-approved drug library using bacterial reporter systems with the Bvg+-specific and Bvg--specific promoters. Lonidamine directly bound to the VFT2 domain of BvgS and inactivated the BvgAS system at concentrations as low as 50 nM, which was at least 2000- to 20,000-fold lower than the effective concentrations of known modulators. Lonidamine significantly reduced the adherence of B. pertussis to cultured cells but unexpectedly exacerbated bacterial colonization of the mouse nasal septum. These results provide insights into the structural requirements for BvgAS modulators and the role of Bvg phenotypes in the establishment of infection.
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Progenitor effect in the spleen drives early recovery via universal hematopoietic cell inflation. International journal
Takao Yogo, Hans Jiro Becker, Takaharu Kimura, Satoshi Iwano, Takahiro Kuchimaru, Atsushi Miyawaki, Tomomasa Yokomizo, Toshio Suda, Atsushi Iwama, Satoshi Yamazaki
Cell reports 44 ( 2 ) 115241 - 115241 2025.2
Language：English Publishing type：Research paper (scientific journal)
Hematopoietic stem cells (HSCs) possess the capacity to regenerate the entire hematopoietic system. However, the precise HSC dynamics in the early post-transplantation phase remain an enigma. Clinically, the initial hematopoiesis in the post-transplantation period is critical, necessitating strategies to accelerate hematopoietic recovery. Here, we uncovered the spatiotemporal dynamics of early active hematopoiesis, "hematopoietic cell inflation," using a highly sensitive in vivo imaging system. Hematopoietic cell inflation occurs in three peaks in the spleen after transplantation, with common myeloid progenitors (CMPs), notably characterized by HSC-like signatures, playing a central role. Leveraging these findings, we developed expanded CMPs (exCMPs), which exhibit a gene expression pattern that selectively proliferates in the spleen and promotes hematopoietic expansion. Moreover, universal exCMPs supported early hematopoiesis in allogeneic transplantation. Human universal exCMPs have the potential to be a viable therapeutic enhancement for all HSC transplant patients.
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Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection Reviewed
Tomokazu Tamura, Hayato Ito, Shiho Torii, Lei Wang, Rigel Suzuki, Shuhei Tsujino, Akifumi Kamiyama, Yoshitaka Oda, Masumi Tsuda, Yuhei Morioka, Saori Suzuki, Kotaro Shirakawa, Kei Sato, Kumiko Yoshimatsu, Yoshiharu Matsuura, Satoshi Iwano, Shinya Tanaka, Takasuke Fukuhara
iScience 27 ( 5 ) 109647 - 109647 2024.5
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV
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Misa Minegishi, Takahiro Kuchimaru, Kaori Nishikawa, Takayuki Isagawa, Satoshi Iwano, Kei Iida, Hiromasa Hara, Shizuka Miura, Marika Sato, Shigeaki Watanabe, Akifumi Shiomi, Yo Mabuchi, Hiroshi Hamana, Hiroyuki Kishi, Tatsuyuki Sato, Daigo Sawaki, Shigeru Sato, Yutaka Hanazono, Atsushi Suzuki, Takahide Kohro, Tetsuya Kadonosono, Tomomi Shimogori, Atsushi Miyawaki, Norihiko Takeda, Hirofumi Shintaku, Shinae Kizaka-Kondoh, Satoshi Nishimura
Nature Communications 14 ( 1 ) 8031 2023.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC
Abstract
Cancer cells inevitably interact with neighboring host tissue-resident cells during the process of metastatic colonization, establishing a metastatic niche to fuel their survival, growth, and invasion. However, the underlying mechanisms in the metastatic niche are yet to be fully elucidated owing to the lack of methodologies for comprehensively studying the mechanisms of cell–cell interactions in the niche. Here, we improve a split green fluorescent protein (GFP)-based genetically encoded system to develop secretory glycosylphosphatidylinositol-anchored reconstitution-activated proteins to highlight intercellular connections (sGRAPHIC) for efficient fluorescent labeling of tissue-resident cells that neighbor on and putatively interact with cancer cells in deep tissues. The sGRAPHIC system enables the isolation of metastatic niche-associated tissue-resident cells for their characterization using a single-cell RNA sequencing platform. We use this sGRAPHIC-leveraged transcriptomic platform to uncover gene expression patterns in metastatic niche-associated hepatocytes in a murine model of liver metastasis. Among the marker genes of metastatic niche-associated hepatocytes, we identify Lgals3, encoding galectin-3, as a potential pro-metastatic factor that accelerates metastatic growth and invasion.DOI： 10.1038/s41467-023-43855-2
Other Link： https://www.nature.com/articles/s41467-023-43855-2
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Toshiaki Nakashiba, Katsunori Ogoh, Satoshi Iwano, Takashi Sugiyama, Saori Mizuno-Iijima, Kenichi Nakashima, Seiya Mizuno, Fumihiro Sugiyama, Atsushi Yoshiki, Atsushi Miyawaki, Kuniya Abe
Lab Animal 52 ( 10 ) 247 - 257 2023.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC
Abstract
In vivo bioluminescence imaging (BLI) has been an invaluable noninvasive method to visualize molecular and cellular behaviors in laboratory animals. Bioluminescent reporter mice harboring luciferases for general use have been limited to a classical luciferase, Luc2, from Photinus pyralis, and have been extremely powerful for various in vivo studies. However, applicability of reporter mice for in vivo BLI could be further accelerated by increasing light intensity through the use of other luciferases and/or by improving the biodistribution of their substrates in the animal body. Here we created two Cre-dependent reporter mice incorporating luciferases oFluc derived from Pyrocoeli matsumurai and Akaluc, both of which had been reported previously to be brighter than Luc2 when using appropriate substrates; we then tested their bioluminescence in neural tissues and other organs in living mice. When expressed throughout the body, both luciferases emitted an intense yellow (oFluc) or far-red (Akaluc) light easily visible to the naked eye. oFluc and Akaluc were similarly bright in the pancreas for in vivo BLI; however, Akaluc was superior to oFluc for brain imaging, because its substrate, AkaLumine-HCl, was distributed to the brain more efficiently than the oFluc substrate, d-luciferin. We also demonstrated that the lights produced by oFluc and Akaluc were sufficiently spectrally distinct from each other for dual-color imaging in a single living mouse. Taken together, these novel bioluminescent reporter mice are an ideal source of cells with bright bioluminescence and may facilitate in vivo BLI of various tissues/organs for preclinical and biomedical research in combination with a wide variety of Cre-driver mice.DOI： 10.1038/s41684-023-01238-6
Other Link： https://www.nature.com/articles/s41684-023-01238-6
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A non-invasive system to monitor in vivo neural graft activity after spinal cord injury Reviewed International journal
Kentaro Ago, Narihito Nagoshi, Kent Imaizumi, Takahiro Kitagawa, Momotaro Kawai, Keita Kajikawa, Reo Shibata, Yasuhiro Kamata, Kota Kojima, Munehisa Shinozaki, Takahiro Kondo, Satoshi Iwano, Atsushi Miyawaki, Masanari Ohtsuka, Haruhiko Bito, Kenta Kobayashi, Shinsuke Shibata, Tomoko Shindo, Jun Kohyama, Morio Matsumoto, Masaya Nakamura, Hideyuki Okano
Communications Biology 5 ( 1 ) 803 - 803 2022.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC
Abstract
Expectations for neural stem/progenitor cell (NS/PC) transplantation as a treatment for spinal cord injury (SCI) are increasing. However, whether and how grafted cells are incorporated into the host neural circuit and contribute to motor function recovery remain unknown. The aim of this project was to establish a novel non-invasive in vivo imaging system to visualize the activity of neural grafts by which we can simultaneously demonstrate the circuit-level integration between the graft and host and the contribution of graft neuronal activity to host behaviour. We introduced Akaluc, a newly engineered luciferase, under the control of enhanced synaptic activity-responsive element (E-SARE), a potent neuronal activity-dependent synthetic promoter, into NS/PCs and engrafted the cells into SCI model mice. Through the use of this system, we found that the activity of grafted cells was integrated with host behaviour and driven by host neural circuit inputs. This non-invasive system is expected to help elucidate the therapeutic mechanism of cell transplantation treatment for SCI.DOI： 10.1038/s42003-022-03736-8
Other Link： https://www.nature.com/articles/s42003-022-03736-8
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Functional visualization of NK Cell-mediated killing of metastatic single tumor cells International journal
Ichise Hiroshi, Tsukamoto Shoko, Hirashima Tsuyoshi, Konishi Yoshinobu, Oki Choji, Tsukiji Shinya, Iwano Satoshi, Miyawaki Atsushi, Sumiyama Kenta, Terai Kenta, Matsuda Michiyuki
eLife 11 2022.2
Language：English Publishing type：Research paper (scientific journal)
Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is unknown. Here we have combined ultra-sensitive bioluminescence imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that 50% of NK-tumor cell encounters lead to tumor cell death in the first 4 hrs after tumor cell arrival, but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. During this 24 hrs period, the probability of ERK activation in NK cells upon encountering the tumor cells was decreased from 68% to 8%, which correlated with the loss of the activating ligand CD155/PVR/Necl5 from the tumor cell surface. Thus, by quantitatively visualizing the NK-tumor cell interaction at the early stage of metastasis, we have revealed the crucial parameters of NK cell immune surveillance in the lung.
DOI： 10.7554/eLife.76269
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Kamiya Genta, Kitada Nobuo, Saito-Moriya Ryohei, Obata Rika, Iwano Satoshi, Miyawaki Atsushi, Hirano Takashi, Maki Shojiro A.
Chemistry Letters 50 ( 8 ) 1523 - 1525 2021.5
Language：English Publishing type：Research paper (scientific journal) Publisher：The Chemical Society of Japan
Firefly bioluminescence, which produces high-efficiency light, is widely used in life science applications. For <i>in vivo</i> bioluminescence imaging, the near-infrared range (650–900 nm) is suitable because of its high permeability in deep biological tissues. In this study, we synthesized new luciferin analogues that emit light at 765 nm using <i>Photinus pyralis</i> luciferase.
DOI： 10.1246/cl.210261
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DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes. Reviewed International journal
Kensuke Kayamori, Yurie Nagai, Cheng Zhong, Satoshi Kaito, Daisuke Shinoda, Shuhei Koide, Wakako Kuribayashi, Motohiko Oshima, Yaeko Nakajima-Takagi, Masayuki Yamashita, Naoya Mimura, Hans Jiro Becker, Kiyoko Izawa, Satoshi Yamazaki, Satoshi Iwano, Atsushi Miyawaki, Ryoji Ito, Kaoru Tohyama, William Lennox, Josephine Sheedy, Marla Weetall, Emiko Sakaida, Koutaro Yokote, Atsushi Iwama
Blood advances 5 ( 2 ) 438 - 450 2021.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Blood Advances
Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We investigated the efficacy of PTC299, a novel DHODH inhibitor, for myelodysplastic syndrome (MDS). PTC299 inhibited the proliferation of MDS cell lines, and this was rescued by exogenous uridine, which bypasses de novo pyrimidine synthesis. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents, such as decitabine, to inhibit the growth of MDS cells. This synergistic effect was confirmed in primary MDS samples. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Mechanistically, a treatment with PTC299 induced intra-S-phase arrest followed by apoptotic cell death. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. RNA-seq data revealed the marked downregulation of MYC target gene sets with PTC299 exposure. Transfection of MDS cell lines with MYC largely attenuated the growth inhibitory effects of PTC299, suggesting MYC as one of the major targets of PTC299. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS.
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Efficacy of the novel tubulin polymerization inhibitor PTC‐028 for myelodysplastic syndrome Reviewed
Cheng Zhong, Kensuke Kayamori, Shuhei Koide, Daisuke Shinoda, Motohiko Oshima, Yaeko Nakajima‐Takagi, Yurie Nagai, Naoya Mimura, Emiko Sakaida, Satoshi Yamazaki, Satoshi Iwano, Atsushi Miyawaki, Ryoji Ito, Kaoru Tohyama, Kiyoshi Yamaguchi, Yoichi Furukawa, William Lennox, Josephine Sheedy, Marla Weetall, Atsushi Iwama
Cancer Science 111 ( 12 ) 4336 - 4347 2020.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley
Monomer tubulin polymerize into microtubules, which are highly dynamic and play a critical role in mitosis. Therefore, microtubule dynamics are an important target for anticancer drugs. The inhibition of tubulin polymerization or depolymerization was previously targeted and exhibited efficacy against solid tumors. The novel small molecule PTC596 directly binds tubulin, inhibits microtubule polymerization, downregulates MCL-1, and induces p53-independent apoptosis in acute myeloid leukemia cells. We herein investigated the efficacy of PTC-028, a structural analog of PTC596, for myelodysplastic syndrome (MDS). PTC-028 suppressed growth and induced apoptosis in MDS cell lines. The efficacy of PTC028 in primary MDS samples was confirmed using cell proliferation assays. PTC-028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit growth and induce apoptosis in MDS cells. Mechanistically, a treatment with PTC-028 induced G2/M arrest followed by apoptotic cell death. We also assessed the efficacy of PTC-028 in a xenograft mouse model of MDS using the MDS cell line, MDS-L, and the AkaBLI bioluminescence imaging system, which is composed of AkaLumine-HCl and Akaluc. PTC-028 prolonged the survival of mice in xenograft models. The present results suggest a chemotherapeutic strategy for MDS through the disruption of microtubule dynamics in combination with DNA hypomethylating agents.
DOI： 10.1111/cas.14684
Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14684
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Development of near‐infrared firefly luciferin analogue reacted with wild‐type and mutant luciferases Reviewed International journal
Nobuo Kitada, Ryohei Saito, Rika Obata, Satoshi Iwano, Kazuma Karube, Atsushi Miyawaki, Takashi Hirano, Shojiro A. Maki
Chirality 32 ( 7 ) 922 - 931 2020.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley
Interestingly, only the D-form of firefly luciferin produces light by luciferin-luciferase (L-L) reaction. Certain firefly luciferin analogues with modified structures maintain bioluminescence (BL) activity; however, all L-form luciferin analogues show no BL activity. To this date, our group has developed luciferin analogues with moderate BL activity that produce light of various wavelengths. For in vivo bioluminescence imaging, one of the important factors for detection sensitivity is tissue permeability of the number of photons emitted by L-L reaction, and the wavelengths of light in the near-infrared (NIR) range (700-900 nm) are most appropriate for the purpose. Some NIR luciferin analogues by us had performance for in vivo experiments to make it possible to detect photons from deep target tissues in mice with high sensitivity, whereas only a few of them can produce NIR light by the L-L reactions with wild-type luciferase and/or mutant luciferase. Based on the structure-activity relationships, we designed and synthesized here a luciferin analogue with the 5-allyl-6-dimethylamino-2-naphthylethenyl moiety. This analogue exhibited NIR BL emissions with wild-type luciferase (λmax = 705 nm) and mutant luciferase AlaLuc (λmax = 655 nm).
DOI： 10.1002/chir.23236
Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/chir.23236