Hashimoto, Hisayuki

写真a

Affiliation

School of Medicine, Joint Research Laboratory for Medical Innovation in Heart Disease （Shinanomachi）

Position

Project Senior Assistant Professor (Non-tenured)/Project Assistant Professor (Non-tenured)/Project Lecturer (Non-tenured)

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Other Affiliation 【 Display / hide 】

  • 医学部, 循環器内科学教室, 特任講師

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Career 【 Display / hide 】

  • 2006.04
    -
    2008.03

    栃木県済生会宇都宮病院, 初期臨床研修医

  • 2008.04
    -
    2009.03

    慶應義塾大学病院 内科学教室, 専修医

  • 2009.04
    -
    2011.03

    Keio University, School of Medicine, 「幹細胞医学のための教育研究拠点」研究員

  • 2011.04
    -
    2012.03

    Keio University, 医学研究科, 助教（研究奨励）

  • 2012.04
    -
    2014.03

    Keio University, School of Medicine Department of Internal Medicine (Cardiology), 助教

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Academic Background 【 Display / hide 】

  • 1998.04
    -
    2000.03

    慶應義塾高等学校

  • 2000.04
    -
    2006.03

    Keio University, School of Medicine

  • 2008.04
    -
    2012.03

    Keio University, Graduate School of Medicine, 内科学

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Academic Degrees 【 Display / hide 】

  • Doctor(Medicine), Keio University, Coursework, 2014.09

    Time-lapse imaging of cell cycle dynamics during development in living cardiomyocyte

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Licenses and Qualifications 【 Display / hide 】

  • 医師免許, 2006

  • 日本内科学会　認定内科医, 2009

  • 日本循環器学会　循環器専門医, 2013

  • Educational Commission for Foreign Medical Graduates Certificate, 2015

  • 日本内科学会　総合内科専門医, 2019

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Research Areas 【 Display / hide 】

  • Life Science / Molecular biology (エピジェネティクス)

  • Life Science / Genome biology

  • Life Science / Developmental biology (心臓発生)

  • Life Science / Anatomy

  • Life Science / Pathological biochemistry

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Research Keywords 【 Display / hide 】

  • エピジェネティクス

  • リプログラミング

  • 再生医療

  • 分子生物学

  • 幹細胞

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Papers 【 Display / hide 】

  • Machine learning in cardiology: Clinical application and basic research.

    Komuro J, Kusumoto D, Hashimoto H, Yuasa S

    Journal of cardiology （Journal of Cardiology)  82 （ 2 ） 128 - 133 2023.08

    ISSN  0914-5087

    　View Summary

    Machine learning is a subfield of artificial intelligence. The quality and versatility of machine learning have been rapidly improving and playing a critical role in many aspects of social life. This trend is also observed in the medical field. Generally, there are three main types of machine learning: supervised, unsupervised, and reinforcement learning. Each type of learning is adequately selected for the purpose and type of data. In the field of medicine, various types of information are collected and used, and research using machine learning is becoming increasingly relevant. Many clinical studies are conducted using electronic health and medical records, including in the cardiovascular area. Machine learning has also been applied in basic research. Machine learning has been widely used for several types of data analysis, such as clustering of microarray analysis and RNA sequence analysis. Machine learning is essential for genome and multi-omics analyses. This review summarizes the recent advancements in the use of machine learning in clinical applications and basic cardiovascular research.

  • MEF2C/p300-mediated epigenetic remodeling promotes the maturation of induced cardiomyocytes

    Hidenori Kojima, Taketaro Sadahiro, Naoto Muraoka, Hiroyuki Yamakawa, Hisayuki Hashimoto, Ryota Ishii, Masahiko Gosho, Yuto Abe, Yu Yamada, Koji Nakano, Seiichiro Honda, Ryo Fujita, Tatsuya Akiyama, Yoichi Sunagawa, Tatsuya Morimoto, Toshifumi Tsukahara, Hiroyuki Hirai, Keiichi Fukuda, Masaki Ieda

    Stem Cell Reports （Elsevier BV)  18 （ 6 ） 1274 - 1283 2023.06

    ISSN  2213-6711

    　View Summary

    Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation.

  • Development of non-bias phenotypic drug screening for cardiomyocyte hypertrophy by image segmentation using deep learning

    Jin Komuro, Yuta Tokuoka, Tomohisa Seki, Dai Kusumoto, Hisayuki Hashimoto, Toshiomi Katsuki, Takahiro Nakamura, Yohei Akiba, Thukaa Kuoka, Mai Kimura, Takahiro Yamada, Keiichi Fukuda, Akira Funahashi, Shinsuke Yuasa

    Biochemical and Biophysical Research Communications （Elsevier BV)  632   181 - 188 2022.12

    ISSN  0006-291X

    　View Summary

    The number of patients with heart failure and related deaths is rapidly increasing worldwide, making it a major problem. Cardiac hypertrophy is a crucial preliminary step in heart failure, but its treatment has not yet been fully successful. In this study, we established a system to evaluate cardiomyocyte hypertrophy using a deep learning-based high-throughput screening system and identified drugs that inhibit it. First, primary cultured cardiomyocytes from neonatal rats were stimulated by both angiotensin II and endothelin-1, and cellular images were captured using a phase-contrast microscope. Subsequently, we used a deep learning model for instance segmentation and established a system to automatically and unbiasedly evaluate the cardiomyocyte size and perimeter. Using this system, we screened 100 FDA-approved drugs library and identified 12 drugs that inhibited cardiomyocyte hypertrophy. We focused on ezetimibe, a cholesterol absorption inhibitor, that inhibited cardiomyocyte hypertrophy in a dose-dependent manner in vitro. Additionally, ezetimibe improved the cardiac dysfunction induced by pressure overload in mice. These results suggest that the deep learning-based system is useful for the evaluation of cardiomyocyte hypertrophy and drug screening, leading to the development of new treatments for heart failure.

  • The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure.

    Shogo Ito, Hisayuki Hashimoto, Hiroyuki Yamakawa, Dai Kusumoto, Yohei Akiba, Takahiro Nakamura, Mizuki Momoi, Jin Komuro, Toshiomi Katsuki, Mai Kimura, Yoshikazu Kishino, Shin Kashimura, Akira Kunitomi, Mark Lachmann, Masaya Shimojima, Gakuto Yozu, Chikaaki Motoda, Tomohisa Seki, Tsunehisa Yamamoto, Yoshiki Shinya, Takahiro Hiraide, Masaharu Kataoka, Takashi Kawakami, Kunimichi Suzuki, Kei Ito, Hirotaka Yada, Manabu Abe, Mizuko Osaka, Hiromi Tsuru, Masayuki Yoshida, Kenji Sakimura, Yoshihiro Fukumoto, Michisuke Yuzaki, Keiichi Fukuda, Shinsuke Yuasa

    Nature communications （Nature Communications)  13 （ 1 ） 5409 - 5409 2022.09

    　View Summary

    Failure of the right ventricle plays a critical role in any type of heart failure. However, the mechanism remains unclear, and there is no specific therapy. Here, we show that the right ventricle predominantly expresses alternative complement pathway-related genes, including Cfd and C3aR1. Complement 3 (C3)-knockout attenuates right ventricular dysfunction and fibrosis in a mouse model of right ventricular failure. C3a is produced from C3 by the C3 convertase complex, which includes the essential component complement factor D (Cfd). Cfd-knockout mice also show attenuation of right ventricular failure. Moreover, the plasma concentration of CFD correlates with the severity of right ventricular failure in patients with chronic right ventricular failure. A C3a receptor (C3aR) antagonist dramatically improves right ventricular dysfunction in mice. In summary, we demonstrate the crucial role of the C3-Cfd-C3aR axis in right ventricular failure and highlight potential therapeutic targets for right ventricular failure.

  • The histone reader PHF7 cooperates with the SWI/SNF complex at cardiac super enhancers to promote direct reprogramming.

    Glynnis A Garry, Svetlana Bezprozvannaya, Kenian Chen, Huanyu Zhou, Hisayuki Hashimoto, Maria Gabriela Morales, Ning Liu, Rhonda Bassel-Duby, Eric N Olson

    Nature cell biology （Nature Cell Biology)  23 （ 5 ） 467 - 475 2021.05

    ISSN  1465-7392

    　View Summary

    Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through overexpression of the transcription factors Gata4, Mef2c and Tbx5; later, Hand2 and Akt1 were found to further enhance this process1-5. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogramme adult fibroblasts6,7. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor8. Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, it increases chromatin accessibility and transcription factor binding at these sites. Furthermore, PHF7 recruits cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. Importantly, PHF7 achieves efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic readers, such as PHF7, in harnessing chromatin remodelling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Epigenetic barrier against the propagation of fluctuating gene expression in embryonic stem cells

    Saito Y., Kunitomi A., Seki T., Tohyama S., Kusumoto D., Takei M., Kashimura S., Hashimoto H., Yozu G., Motoda C., Shimojima M., Egashira T., Oda M., Fukuda K., Yuasa S.

    FEBS Letters (FEBS Letters)  591 ( 18 ) 2879 - 2889 2017.09

    ISSN  00145793

    　View Summary

    © 2017 Federation of European Biochemical Societies The expression of pluripotency genes fluctuates in a population of embryonic stem (ES) cells and the fluctuations in the expression of some pluripotency genes correlate. However, no correlation in the fluctuation of Pou5f1, Zfp42, and Nanog expression was observed in ES cells. Correlation between Pou5f1 and Zfp42 fluctuations was demonstrated in ES cells containing a knockout in the NuRD component Mbd3. ES cells containing a triple knockout in the DNA methyltransferases Dnmt1, Dnmt3a, and Dnmt3b showed correlation between the fluctuation of Pou5f1, Zfp42, and Nanog gene expression. We suggest that an epigenetic barrier is key to preventing the propagation of fluctuating pluripotency gene expression in ES cells.

  • Induction of Cardiac Cell Types by Direct Reprogramming

    Hisayuki Hashimoto, Huanyu Zhou, Maria G. Morales, Maria Abad, Rhonda Bassel-Duby, Eric N. Olson

    CIRCULATION RESEARCH (LIPPINCOTT WILLIAMS & WILKINS)  119 ( 12 ) E168 - E168 2016.12

    Research paper, summary (international conference), Joint Work,  ISSN  0009-7330

  • Novel Method 'Fucci' Elucidated the Cardiomyocyte Cell Cycle Dynamics in Various Life Stages

    Hisayuki Hashimoto, Shinsuke Yuasa, Shugo Tohyama, Tomohisa Seki, Toru Egashira, Kojiro Yae, Dai Kusumoto, Masaki Kodaira, Fumiyuki Hattori, Naoto Muraoka, Hidenori Tabata, Kazunori Nakajima, Asako Sakaue-Sawano, Atsushi Miyawaki, Keiichi Fukuda

    CIRCULATION (LIPPINCOTT WILLIAMS & WILKINS)  122 ( 21 )  2010.11

    Research paper, summary (international conference), Joint Work,  ISSN  0009-7322

  • ヒトiPS由来心筋細胞の電気生理学的特性について

    遠山 周吾, 村田 光繁, 黒川 洵子, Fernando Lopez-Redondo, 服部 文幸, 水澤 美香, 山川 裕之, 橋本 寿之, 江頭 徹, 関 朋久, 扇野 泰行, 八戸 宏二郎, 湯浅 慎介, 福田 恵一

    心電図 ((一社)日本不整脈心電学会)  30 ( Suppl.4 ) S - 4 2010.09

    Other, Joint Work,  ISSN  0285-1660

  • Functional Characterization of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

    Shugo Tohyama, Mitsushige Murata, Fumiyuki Hattori, Tomofumi Tanaka, Hao Chen, Hiromi Yamashita, Yusuke Sato, Toru Egashira, Tomohisa Seki, Hisayuki Hashimoto, Yohei Ohno, Yuichi Tamura, Shinsuke Yuasa, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION (LIPPINCOTT WILLIAMS & WILKINS)  120 ( 18 ) S723 - S723 2009.11

    Research paper, summary (international conference), Joint Work,  ISSN  0009-7322

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Presentations 【 Display / hide 】

  • Dissecting the Molecular Mechanism of Cardiac Reprogramming by Epigenetic Analysis

    Hisayuki Hashimoto

    日本再生医療学会, 

    2020.03
    , 

    Oral presentation (invited, special)

  • エピジェネティクス解析を用いた心筋リプログラミングの分子機構の解明

    橋本　寿之

    第40回日本循環制御医学会　総会・学術集会, 

    2019.06
    , 

    Oral presentation (general)

  • Synergistic Activation of the Cardiac Enhancer Landscape During Reprogramming

    Hashimoto Hisayuki

    The 83rd Annual Scientific Meeting of the Japanese Circulation Society, 

    2019.03
    , 

    Oral presentation (general)

  • Induction of Cardiac Cell Types by Direct Reprogramming

    Hashimoto Hisayuki

    American Heart Association Scientific Sessions, 

    2016.11
    , 

    Poster presentation

  • Induction of Diverse Cardiac Cell Types by Direct Reprogramming

    Hashimoto Hisayuki

    American Heart Association Scientific Council on Basic Cardiovascular Sciences, 

    2016.07
    , 

    Oral presentation (invited, special)

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • 細胞移植療法の最適化に向けた生体内移植細胞の非侵襲的検出技術の開発

    2023.06
    -
    2026.03

    日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), No Setting

  • Dissecting the transcriptional network of organogenesis based on reprogramming factors

    2022.04
    -
    2025.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), No Setting

    　View Summary

    我々は線維芽細胞から心筋細胞を作製する直接分化転換法の研究において、幹細胞の多能性維持に働く転写因子Zfp281に非常に強い心筋分化転換作用がある事を見出した。そして予備実験においてZfp281が心筋分化と心臓発生に必須な因子であることも示唆されている。
    よって、本研究ではこのZfp281と心臓形成の予想外な関連性に着目し、様々な遺伝子改変マウス及び遺伝子発現・エピゲノム解析を用いて、Zfp281を中心とした心臓形成の新たな転写制御機構を明らかにする。そして、最終的には研究成果を心疾患の新たな分子機序解明や心臓再生技術の開発へと発展させることを目指す。

  • 中胚葉において循環器形成細胞が誘導される分子基盤解明

    2022
    -
    2023

    公益財団法人 循環器病研究振興財団, 山内進循環器病研究助成, Principal investigator

  • エピゲノム編集による心筋分化転換法の確立

    2021
    -
    2023

    日本循環器学会, 基礎研究助成, Principal investigator

  • SARS-CoV-2 細胞侵入受容体の発現調節経路を標的としたCOVID-19 の新規治療戦略

    2020
    -
    2021

    公益財団法人 東京生化学研究会, 研究奨励金, Principal investigator

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Awards 【 Display / hide 】

  • Basic Cardiovascular Sciences Scientific Session 2022 Outstanding Early Career Investigator Award

    2022.07, American Heart Association

  • Basic Cardiovascular Sciences Scientific Session 2022 Paul Dudley White International Scholar

    2022.07, American Heart Association

  • 医学研究賞

    橋本 寿之, 2021.03, 東京都医師会

  • 循環器再生医科学賞

    橋本 寿之, 2020.08, 日本循環器学会

  • Keio University School of Medicine Alumni Association (Sanshikai) Young Investigator Award

    2020.04, Keio University

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Courses Taught 【 Display / hide 】

  • PATHOPHYSIOLOGICAL ISSUES IN CHRONIC CARE

    2024

  • PATHOPHYSIOLOGICAL ISSUES IN CHRONIC CARE

    2023

  • PHYSICAL ASSESSMENT

    2022

  • PATHOPHYSIOLOGICAL ISSUES IN CHRONIC CARE

    2022

  • CLINICAL ENGINEERING AND SAFETY CONTROL IN HEALTH CARE

    2022

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Courses Previously Taught 【 Display / hide 】

  • Medical Engineering in Cardiology

    Keio University School of Nursing

    2022
    -
    Present
    , 

    Postgraduate

  • Chronic Pathophysiology

    Keio University School of Nursing

    2022
    -
    Present
    , 

    Undergraduate (specialized)

  • Phyisical Assessment in Cardiology

    Keio University School of Nursing

    2022
    -
    Present
    , 

    Postgraduate

  • OSCE(Objective Structured Clinical Examination)

    Keio University

    2018
    -
    Present

  • Cardiology

    Keio University

    2018
    -
    Present

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Educational Activities and Special Notes 【 Display / hide 】

  • OSCE

    2020

    , Special Affairs about A person who has work experience

  • 医学部カリキュラム委員

    2019
    -
    2020

    , Special Affairs

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Memberships in Academic Societies 【 Display / hide 】

  • 日本再生医療学会, 

    2020.03
    -
    Present
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