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Kenji Inoue

Section

Institute of Medical Research

Job title

Senior Assistant Professor

Degree

PhD in Dental Science (Tokyo Dental College)

researchmap

https://researchmap.jp/inouekenji

J-GLOBAL ID

202501009342826741

ORCID

https://orcid.org/0000-0003-3946-9538

Profile

研究スキル・専門技術（Training-based Expertise）：

１．非ウイルス性ハイブリッドベクターの構築・取扱い・遺伝子導入

　・ニューヨーク大学新規ベクターの開発、臨床モデルマウスへの応用（2018-2025）
　・口腔癌モデルマウスへの遺伝子治療（2018-2025）

２．ウイルスベクター（AAV・レンチウイルス）の構築・取扱い・遺伝子導入

　・国立生理学研究所ウイルスベクター開発部門技術研修（2015）
　・理化学研究所バイオリソース研究センターウイルスベクターハンドリング講習（2014）
　・単なる使用経験にとどまらず、ベクター設計から導入条件最適化まで自立して遂行可能

３．逆行性・神経指向性ウイルスを含む遺伝子導入技術

　・国立生理学研究所技術研修コース（2015）
　・神経系を対象とした遺伝子操作・機能解析研究への即応性を有する

４．CRISPR/Cas9によるゲノム編集技術

　・Life Technologies Japan 主催 CRISPR/Cas9ゲノム編集技術集中ハンズオントレーニング（2016）
　・設計・導入・検証まで一貫して実施可能な実践的スキル

５．RNAi導入および遺伝子発現解析

　・Life Technologies Japan 技術トレーニング（2014）
　・遺伝子機能評価を目的としたロス・オブ・ファンクション解析に習熟

６．ヒト・マウスiPS細胞の樹立・培養・維持管理

　・京都大学 iPS細胞研究所（CiRA）実習研修（2013）
　・理化学研究所バイオリソース研究センター iPS細胞培養講習（2013）
　・品質管理を含めた長期培養と実験応用が可能

７．細胞培養（基礎〜応用）に関する体系的専門トレーニング

　・日本組織培養学会認定長期集中トレーニングプログラム修了（2016）
　・動物細胞培養の標準技術を網羅的に習得

８．分子遺伝学・遺伝子工学（DNA・タンパク質工学）

　・東京農工大学遺伝子研究センター専門トレーニング（2015）
　・分子クローニングからタンパク質解析まで対応可能

９．細胞・組織化学的解析

　・日本組織細胞化学会主催ワークショップ修了（2014）
　・IF, IHC, ISH etc.各種形態解析に精通
　・組織レベルでの遺伝子・タンパク質発現解析に精通

10．バイオフォトニクス・光学イメージング技術

　・国立生理学研究所バイオフォトニクス研究班技術研修（2024）
　・生体組織の高次機能解析に応用可能な最新イメージング知識

11．国際研究環境での研究遂行力

　・Stanford University School of Medicine, Department of Genetics（2012）
　・New York University College of Dentistry, Translational Research Center（2018-2025）
　・ニューヨーク大学多国籍研究チームにおける実験遂行・コミュニケーション能力を涵養

Research History 7

2025/12 - Present

国立大学法人東北大学　医学イノベーション研究所（SiRIUS）　講師
2022/10 - 2025/11

New York University College of Dentistry　Translational Research Center　Assistant Research Scientist
2018/01 - 2022/09

New York University　Postdoctoral Associate
2016/04 - 2017/12

Tokyo Dental College
2013/04 - 2015/03

Tokyo Dental College
2011/04 - 2012/03

National Hospital Organization, East Saitama Hospital
2009/04 - 2011/03

Keio University　School of Medicine Department of Dentistry and Oral Surgery

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Education 2

Tokyo Dental College

2012/04 - 2016/03
Tokyo Dental College

2003/04 - 2009/03

Papers 21

Non-viral gene delivery systems in the treatment of oral cancers: a promising future

Seiichi Yamano, Kenji Inoue

Nanomedicine　2025/08/18

DOI： 10.1080/17435889.2025.2503693 　

ISSN： 1743-5889 1748-6963
Application of Gene Therapy to Oral Diseases

Seiichi Yamano, Kenji Inoue, Yoichiro Taguchi

Pharmaceutics　2025/06/30

DOI： 10.3390/pharmaceutics17070859 　
Application of Gene Therapy to Oral Diseases

Seiichi Yamano, Kenji Inoue, Yoichiro Taguchi

Pharmaceutics　2025/06

DOI： 10.3390/pharmaceutics17070859 　
Developmental Endothelial Locus-1 Promotes Osteoclast Differentiation and Activation

Kentaro Imamura, Keita Tachi, Tadahiro Takayama, Hironori Kasai, Ryutaro Shohara, Kenji Inoue, Yoichiro Taguchi, Saki Nakane-Koyachi, Atsushi Saito, Seiichi Yamano

International Journal of Molecular Sciences　2025/03/16

DOI： 10.3390/ijms26062673 　
TRPV4 activation in Schwann cells mediates mechanically induced pain of oral cancer

Yatendra Mulpuri, Nguyen H. Tu, Kenji Inoue, Grace Harden, Samuel J. Nicholson, Anisa Seenauth, Yan Huang, Keylin G. Escobar, Yalda Moayedi, Nigel W. Bunnett, Donna G. Albertson, Brian L. Schmidt

Frontiers in Pain Research　2025/03/12

DOI： 10.3389/fpain.2025.1532885 　

ISSN： 2673-561X

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<jats:sec><jats:title>Introduction</jats:title><jats:p>Patients with oral cancer often experience intense functional pain due to mechanical stimulation at the cancer site. The role of mechanosensitive ion channels in oral cancer pain, such as TRPV4, is not fully understood.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>Our objective was to investigate the role of Schwann cell TRPV4 in oral cancer pain.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We examined the impact of TRPV4 inhibition on oral cancer pain in NU/J and C57BL/6J mice injected with human tongue cancer cell line (HSC-3) and mouse oral cancer cell line (MOC2) in the hind paw or tongue. Mechanical and heat sensitivity were assessed using the von Frey and Hargreaves tests, respectively. TRPV4 expression and functional activity in Schwann cells were analyzed using immunohistochemistry, qRT-PCR, Ca<jats:sup>2+</jats:sup> imaging, and patch-clamp electrophysiology. The effect of TRPV4 activation on Schwann cell responses to mechanical stimulation was evaluated using a piezo stimulator. Conditioned media (CM) from TRPV4-activated Schwann cells were injected into the mouse paw to evaluate the contribution of TRPV4 in Schwann cells to mechanical hypersensitivity.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>TRPV4 inhibition reduced paw cancer mechanical nociception in mice dose-dependently without affecting heat sensitivity. TRPV4 inhibition also decreased facial nociception in tongue cancer mice. TRPV4 was expressed mainly on the plasma membrane of mouse Schwann cells and activation of TRPV4 induced Ca<jats:sup>2+</jats:sup> responses and whole-cell membrane currents in human Schwann cells. Mechanoactivated currents in human Schwann cells were inhibited by the TRPV4 antagonist HC-067047. Schwann cell CM induced mechanical hypersensitivity in mice, which was blocked by pre-treatment with HC-067047.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>TRPV4 activation plays a role in mediating mechanically induced pain of oral cancer.</jats:p></jats:sec>
PAR2 on oral cancer cells and nociceptors contributes to oral cancer pain that can be relieved by nanoparticle-encapsulated AZ3451

Divya Bhansali, Nguyen H. Tu, Kenji Inoue, Shavonne Teng, Tianyu Li, Hung D. Tran, Dong H. Kim, Jessy Dong, Chloe J. Peach, Badr Sokrat, Dane D. Jensen, John C. Dolan, Seiichi Yamano, Valeria Mezzano Robinson, Nigel W. Bunnett, Donna G. Albertson, Kam W. Leong, Brian L. Schmidt

Biomaterials　2025/03

DOI： 10.1016/j.biomaterials.2024.122874 　
Developmental Endothelial Locus-1 Promotes Osteoclast Differentiation and Activation

Kentaro Imamura, Keita Tachi, Tadahiro Takayama, Hironori Kasai, Ryutaro Shohara, Kenji Inoue, Yoichiro Taguchi, Saki Nakane-Koyachi, Atsushi Saito, Seiichi Yamano

International Journal of Molecular Sciences　2025/03

DOI： 10.3390/ijms26062673 　
The effect of nano hydroxyapatite coating implant surfaces on gene expression and osseointegration

H. Kasai, ET. Bergamo, Íd. Balderrama, K. Imamura, L. Witek, EB. Jalkh, EA. Bonfante, K. Inoue, PG. Coelho, S. Yamano

Medicina Oral Patología Oral y Cirugia Bucal　2024

DOI： 10.4317/medoral.26303 　

ISSN： 1698-6946
Calcitonin Related Polypeptide Alpha Mediates Oral Cancer Pain

Nguyen Huu Tu, Kenji Inoue, Parker K. Lewis, Ammar Khan, Jun Hyeong Hwang, Varun Chokshi, Branka Brukner Dabovic, Shanmugapriya Selvaraj, Aditi Bhattacharya, Zinaida Dubeykovskaya, Nathalie M. Pinkerton, Nigel W. Bunnett, Cynthia A. Loomis, Donna G. Albertson, Brian L. Schmidt

Cells　2023/06/21

DOI： 10.3390/cells12131675 　

ISSN： 2073-4409

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<jats:p>Oral cancer patients suffer pain at the site of the cancer. Calcitonin gene related polypeptide (CGRP), a neuropeptide expressed by a subset of primary afferent neurons, promotes oral cancer growth. CGRP also mediates trigeminal pain (migraine) and neurogenic inflammation. The contribution of CGRP to oral cancer pain is investigated in the present study. The findings demonstrate that CGRP-immunoreactive (-ir) neurons and neurites innervate orthotopic oral cancer xenograft tumors in mice. Cancer increases anterograde transport of CGRP in axons innervating the tumor, supporting neurogenic secretion as the source of CGRP in the oral cancer microenvironment. CGRP antagonism reverses oral cancer nociception in preclinical oral cancer pain models. Single-cell RNA-sequencing is used to identify cell types in the cancer microenvironment expressing the CGRP receptor components, receptor activity modifying protein 1 Ramp1 and calcitonin receptor like receptor (CLR, encoded by Calcrl). Ramp1 and Calcrl transcripts are detected in cells expressing marker genes for Schwann cells, endothelial cells, fibroblasts and immune cells. Ramp1 and Calcrl transcripts are more frequently detected in cells expressing fibroblast and immune cell markers. This work identifies CGRP as mediator of oral cancer pain and suggests the antagonism of CGRP to alleviate oral cancer pain.</jats:p>
Peroxisome proliferator-activated receptor gamma agonist ELB00824 suppresses oxaliplatin-induced pain, neuronal hypersensitivity, and oxidative stress

Morgan Zhang, Min Hu, Sascha R.A. Alles, Marena A. Montera, Ian Adams, Maria D. Santi, Kenji Inoue, Nguyen Huu Tu, Karin N. Westlund, Yi Ye

Neuropharmacology　2022/11

DOI： 10.1016/j.neuropharm.2022.109233 　

ISSN： 0028-3908
Identification of Novel Regulator Involved in Differentiation of Mouse iPS Cells into Odontoblast-like Cells

Kenji Inoue, Kenichi Matsuzaka, Takashi Inoue

The Bulletin of Tokyo Dental College　2022

DOI： 10.2209/tdcpublication.2021-0045 　

ISSN： 0040-8891
Cathepsin S Evokes PAR2-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models

Nguyen Huu Tu, Kenji Inoue, Elyssa Chen, Bethany M. Anderson, Caroline M. Sawicki, Nicole N. Scheff, Hung D. Tran, Dong H. Kim, Robel G. Alemu, Lei Yang, John C. Dolan, Cheng Z. Liu, Malvin N. Janal, Rocco Latorre, Dane D. Jensen, Nigel W. Bunnett, Laura E. Edgington-Mitchell, Brian L. Schmidt

Cancers　2021/09/19

DOI： 10.3390/cancers13184697 　

ISSN： 2072-6694

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<jats:p>Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR2) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR2. We report here a role for cathepsin S in PAR2-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR2 in Nav1.8-positive neurons (Par2Nav1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR2 on neurons.</jats:p>
Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2

Nguyen Huu Tu, Dane D. Jensen, Bethany M. Anderson, Elyssa Chen, Nestor N. Jimenez-Vargas, Nicole N. Scheff, Kenji Inoue, Hung D. Tran, John C. Dolan, Tamaryn A. Meek, Morley D. Hollenberg, Cheng Z. Liu, Stephen J. Vanner, Malvin N. Janal, Nigel W. Bunnett, Laura E. Edgington-Mitchell, Brian L. Schmidt

The Journal of Neuroscience　2021/01/06

DOI： 10.1523/jneurosci.1211-20.2020 　

ISSN： 0270-6474 1529-2401

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<jats:p>Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR<jats:sub>2</jats:sub>) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR<jats:sub>2</jats:sub>-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared with matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR<jats:sub>2</jats:sub>in Na<jats:sub>V</jats:sub>1.8-positive neurons (<jats:italic>Par<jats:sub>2</jats:sub>Na<jats:sub>v</jats:sub>1.8</jats:italic>), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1.<jats:italic>Par<jats:sub>2</jats:sub>Na<jats:sub>v</jats:sub>1.8</jats:italic>and<jats:italic>Lgmn</jats:italic>deletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR<jats:sub>2</jats:sub>-dependent hyperexcitability of trigeminal neurons from WT female mice.<jats:italic>Par<jats:sub>2</jats:sub></jats:italic>deletion, LI-1, and inhibitors of adenylyl cyclase or protein kinase A (PKA) prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N terminus of PAR<jats:sub>2</jats:sub>at Asn<jats:sup>30</jats:sup>↓Arg<jats:sup>31</jats:sup>, proximal to the canonical trypsin activation site. Lgmn activated PAR<jats:sub>2</jats:sub>by biased mechanisms in HEK293 cells to induce Ca<jats:sup>2+</jats:sup>mobilization, cAMP formation, and PKA/protein kinase D (PKD) activation, but not β-arrestin recruitment or PAR<jats:sub>2</jats:sub>endocytosis. Thus, in the acidified OSCC microenvironment, Lgmn activates PAR<jats:sub>2</jats:sub>by biased mechanisms that evoke cancer pain.</jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT</jats:bold>Oral squamous cell carcinoma (OSCC) is one of the most painful cancers. We report that legumain (Lgmn), which exhibits maximal activity in acidic environments, cleaves protease-activated receptor-2 (PAR<jats:sub>2</jats:sub>) on neurons to produce OSCC pain. Active Lgmn was elevated in OSCC patient tumors, compared with matched normal oral tissue. Lgmn evokes pain-like behavior through PAR<jats:sub>2</jats:sub>. Exposure of pain-sensing neurons to Lgmn decreased the current required to generate an action potential through PAR<jats:sub>2</jats:sub>. Inhibitors of adenylyl cyclase and protein kinase A (PKA) prevented the effects of Lgmn. Lgmn activated PAR<jats:sub>2</jats:sub>to induce calcium mobilization, cAMP formation, and activation of protein kinase D (PKD) and PKA, but not β-arrestin recruitment or PAR<jats:sub>2</jats:sub>endocytosis. Thus, Lgmn is a biased agonist of PAR<jats:sub>2</jats:sub>that evokes cancer pain.</jats:p>
Gene therapy for oral disease

Kenji Inoue

Journal of the Academy of Gnathology and Occlusion　2021
Efficient siRNA delivery and gene silencing using a lipopolypeptide hybrid vector mediated by a caveolae-mediated and temperature-dependent endocytic pathway

Hironori Kasai, Kenji Inoue, Kentaro Imamura, Carlo Yuvienco, Jin K. Montclare, Seiichi Yamano

Journal of Nanobiotechnology　2019/12

DOI： 10.1186/s12951-019-0444-8 　

ISSN： 1477-3155
Topography enhances Runx2 expression in outgrowing cells from iPS cell‐derived embryoid bodies

Akram Al‐Wahabi, Tungalag Ser‐Od, Kenji Inoue, Kei Nakajima, Kenichi Matsuzaka, Takashi Inoue

Journal of Biomedical Materials Research Part B: Applied Biomaterials　2019/10

DOI： 10.1002/jbm.b.34321 　

ISSN： 1552-4973 1552-4981

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<jats:title>Abstract</jats:title><jats:p>The effect of differing polystyrene substrate topographies on the osteogenic potential of the outgrowing cells (OGCs) formed from mouse‐induced pluripotent stem (iPS) cells (miPSCs)‐derived embryoid bodies (EBs) was investigated. Polystyrene substrates were sandblasted with 25, 50, and 150 μm aluminum oxide particles to obtain topographies with average Sa values of 0.6, 1.1, and 1.8 μm, respectively. 3D‐SEM was used to evaluate substrate's topographies. Examination was done by scanning electron microscopy (SEM), by immunocytofluorescence (ICF) analysis for vinculin, Runx2 and collagen type I, and by quantitative RT‐PCR (qRT‐PCR) analysis for Runx2 and collagen type I. SEM and ICF analyses revealed that surface roughness caused cells elongation (2, 6, 8, 10 times for the NT, 0.6 μm, 1.1 μm, and 1.8 μm, respectively). Vinculin staining demonstrated how the Sa value affected cellular attachment to the substrate. FA points were randomly distributed on flat surfaces, but rough surfaces resulted in more concentrated FA points on the podia of the cells (11.7, 25.2, 26.7, 16.6 vinculin spots per 20 μm<jats:sup>2</jats:sup> for the NT, 0.6 μm, 1.1 μm, and 1.8 μm, respectively). qRT‐PCR revealed that Runx2 expression was highest on day 16 on surfaces with Sa of 0.6 μm and 1.1 μm. Collagen type I expression increased from day 0 to day 16, no significance was found among the groups. In conclusion, surface topography affects cell shape and expression of early osteogenic potential in OGC, particularly surfaces with Sa values of 0.6 μm and 1.1 μm which showed the highest concentration of FA points on podia. These findings could be utilized in the development of inner surface topographies of scaffolds used with iPSCs. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2288–2296, 2019.</jats:p>
Effect of EDTA-treated dentin on the differentiation of mouse iPS cells into osteogenic/odontogenic lineages <i>in vitro</i> and <i>in vivo </i>

Tungalag SER-OD, Akram AL-WAHABI, Kenji INOUE, Kei NAKAJIMA, Kenichi MATSUZAKA, Takashi INOUE

Dental Materials Journal　2019/09/27

DOI： 10.4012/dmj.2018-161 　

ISSN： 0287-4547 1881-1361
Differentiation behavior of iPS cells cultured on PLGA with osteoinduction medium

Reiko TOKITA, Kei NAKAJIMA, Kenji INOUE, Akram AL-WAHABI, Tungalag SER-OD, Kenichi MATSUZAKA, Takashi INOUE

Dental Materials Journal　2017

DOI： 10.4012/dmj.2016-087 　

ISSN： 0287-4547 1881-1361
Immunohistochemical expression of Ki67 and p53 by cells in odontogenic epithelial islands in the walls of dentigerous cysts and keratocystic odontogenic tumors

Kenji Inoue

Journal of Japanese Society for Evidence and the Dental Professional　2015
Utility of preoperative imaging diagnosis for a malignant tumor of the mandible: a malignant tumor of the mandible is difficult to discriminate from bisphosphonate-related osteonecrosis of the jaw

Takashi Kamio, Akiko Imaizumi, Keiichi Nishikawa, Takeo Shibui, Kenji Inoue, Kenichi Matsuzaka, Junichiro Sakamoto, Tsukasa Sano

Oral Radiology　2014/09

DOI： 10.1007/s11282-013-0161-1 　

ISSN： 0911-6028 1613-9674
Radicular cyst and granuloma: A clinicopathological study of 1590 cases and a literature review.

Kenji Inoue

Journal of Japanese Society for Evidence and the Dental Professional　2014

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