Hashimoto, Hisayuki



School of Medicine, Center for Preventive Medicine (Shinanomachi)



External Links

Other Affiliation 【 Display / hide

  • 医学部, 循環器内科学教室, 助教

Career 【 Display / hide

  • 2006.04

    栃木県済生会宇都宮病院 , 初期臨床研修医

  • 2008.04

    慶應義塾大学病院 , 内科学教室, 専修医

  • 2009.04

    慶應義塾大学, 医学部, グローバルCOEプログラム 研究員

  • 2011.04

    慶應義塾大学, 大学院医学研究科, 助教

  • 2012.04

    慶應義塾大学, 医学部 循環器内科学教室, 助教

display all >>

Academic Background 【 Display / hide

  • 2000.04

    Keio University, 医学部

    University, Graduated

  • 2008.04

    Keio University, 医学部, 医学科

    Graduate School, Withdrawal after completion of doctoral course requirements, Doctoral course

Academic Degrees 【 Display / hide

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

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

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


Research Areas 【 Display / hide

  • Molecular biology (エピジェネティクス)

  • Developmental biology (心臓発生)

  • Cardiovascular medicine (Regenerative Medicine)


Papers 【 Display / hide

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

    Garry GA, Bezprozvannaya S, Chen K, Zhou H, Hashimoto H, Morales MG, Liu N, Bassel-Duby R, Olson EN

    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.

  • Anti-senescent drug screening by deep learning-based morphology senescence scoring.

    Kusumoto D, Seki T, Sawada H, Kunitomi A, Katsuki T, Kimura M, Ito S, Komuro J, Hashimoto H, Fukuda K, Yuasa S

    Nature communications (Nature Communications)  12 ( 1 ) 257 2021.01

     View Summary

    Advances in deep learning technology have enabled complex task solutions. The accuracy of image classification tasks has improved owing to the establishment of convolutional neural networks (CNN). Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Furthermore, it is a potential therapeutic target. Specific molecular markers are used to identify senescent cells. Moreover senescent cells show unique morphology, which can be identified. We develop a successful morphology-based CNN system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells by senescence probability output from pre-trained CNN optimised for the classification of cellular senescence, Deep Learning-Based Senescence Scoring System by Morphology (Deep-SeSMo). Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents. We screen for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug screening and identify four anti-senescent drugs. RNA sequence analysis reveals that these compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Thus, morphology-based CNN system can be a powerful tool for anti-senescent drug screening.

  • Dermal fibroblast-like cells reprogrammed directly from adipocytes in mouse.

    Toyosaki M, Homma K, Suzuki S, Muraoka N, Hashimoto H, Goshima N, Ieda M, Sasaki J

    Scientific reports (Scientific Reports)  10 ( 1 ) 21467 2020.12

     View Summary

    In deep burns, early wound closure is important for healing, and skin grafting is mainly used for wound closure. However, it is difficult to achieve early wound closure in extensive total body surface area deep burns due to the lack of donor sites. Dermal fibroblasts, responsible for dermis formation, may be lost in deep burns. However, fat layers composed of adipocytes, lying underneath the dermis, are retained even in such cases. Direct reprogramming is a novel method for directly reprograming some cells into other types by introducing specific master regulators; it has exhibited appreciable success in various fields. In this study, we aimed to assess whether the transfection of master regulators (ELF4, FOXC2, FOXO1, IRF1, PRRX1, and ZEB1) could reprogram mouse adipocytes into dermal fibroblast-like cells. Our results indicated the shrinkage of fat droplets in reprogrammed mouse adipocytes and their transformation into spindle-shaped dermal fibroblasts. Reduced expression of PPAR-2, c/EBP, aP2, and leptin, the known markers of adipocytes, in RT-PCR, and enhanced expression of anti-ER-TR7, the known anti-fibroblast marker, in immunocytochemistry, were confirmed in the reprogrammed mouse adipocytes. The dermal fibroblast-like cells, reported here, may open up a new treatment mode for enabling early closure of deep burn wounds.

  • Stem Cell Aging in Skeletal Muscle Regeneration and Disease.

    Yamakawa H, Kusumoto D, Hashimoto H, Yuasa S

    International journal of molecular sciences 21 ( 5 )  2020.03

  • Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers.

    Hashimoto H, Wang Z, Garry GA, Malladi VS, Botten GA, Ye W, Zhou H, Osterwalder M, Dickel DE, Visel A, Liu N, Bassel-Duby R, Olson EN

    Cell stem cell (Cell Stem Cell)  25 ( 1 ) 69 - 86.e5 2019.05

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  1934-5909

     View Summary

    © 2019 Elsevier Inc. The cardiogenic transcription factors (TFs) Mef2c, Gata4, and Tbx5 can directly reprogram fibroblasts to induced cardiac-like myocytes (iCLMs), presenting a potential source of cells for cardiac repair. While activity of these TFs is enhanced by Hand2 and Akt1, their genomic targets and interactions during reprogramming are not well studied. We performed genome-wide analyses of cardiogenic TF binding and enhancer profiling during cardiac reprogramming. We found that these TFs synergistically activate enhancers highlighted by Mef2c binding sites and that Hand2 and Akt1 coordinately recruit other TFs to enhancer elements. Intriguingly, these enhancer landscapes collectively resemble patterns of enhancer activation during embryonic cardiogenesis. We further constructed a cardiac reprogramming gene regulatory network and found repression of EGFR signaling pathway genes. Consistently, chemical inhibition of EGFR signaling augmented reprogramming. Thus, by defining epigenetic landscapes these findings reveal synergistic transcriptional activation across a broad landscape of cardiac enhancers and key signaling pathways that govern iCLM reprogramming. Hashimoto and colleagues show that reprogramming factors act in concert at cardiac regulatory elements to directly reprogram mouse fibroblasts into induced cardiac-like myocytes (iCLMs). Moreover, cardiac reprogramming is achieved by activation of endogenous cardiac enhancers that initiate a cardiogenic gene regulatory network.

display all >>

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

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


    Summary of the papers read (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


    Summary of the papers read (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 article, 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

    Summary of the papers read (international conference), Joint Work,  ISSN  0009-7322

display all >>

Presentations 【 Display / hide

  • 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 (general)

  • Induction of Diverse Cardiac Cell Types by Direct Reprogramming

    Hashimoto Hisayuki

    American Heart Association Scientific Council on Basic Cardiovascular Sciences, 2016.07, Oral Presentation(guest/special)

  • A Novel Cardiac ex vivo Culture System Revealed the Elongation of Cell Cycle Phases in Cardiomyocytes During Development

    Hashimoto Hisayuki

    A Novel Cardiac ex vivo Culture System Revealed the Elongation of Cell Cycle Phases in Cardiomyocytes During Development, 2013.06, Oral Presentation(general)

display all >>

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

  • 心臓発生における転写因子ZNF281の心筋分化調節機構の解明


    Keio University, 橋本 寿之, Grant-in-Aid for Early-Career Scientists, Research grant, Principal Investigator

     View Summary

    申請者は転写因子Zinc Finger Protein 281(ZNF281)には、線維芽細胞を心筋様細胞に直接リプログラミングする効率を著明に改善する機能があることを以前明らかにした。本研究ではこのZNF281の心筋誘導作用に着目し、胚性幹細胞(ES細胞)及びマウスを用いて心筋分化と心臓発生におけるZNF281の転写調節機構と作用を解明する。本研究成果はZNF281を利用した新たな心臓再生技術の開発につながる可能性があるだけでなく、心臓形成に関わる新規制御因子を探索するデータベースとしてのリプログラミング法の新たな利用価値を立証することとなる。

  • リプログラミング法を利用した新たな心臓形成転写ネットワークの探索


    公益財団法人 持田記念医学薬学振興財団, 研究助成, 橋本 寿之, 研究助成, Research grant, Principal Investigator

  • オルガノイド形成に向けた心臓刺激伝導系転写制御機構の解明


    公益財団法人 MSD生命科学財団, 生活習慣病領域, 橋本 寿之, 研究助成, Research grant, Principal Investigator

  • リプログラミング法を利用した心臓刺激伝導系誘導因子の探索


    公益財団法人 武田科学振興財団, 医学系研究助成, 橋本 寿之, 研究助成, Research grant, Principal Investigator

  • エピゲノム解析と分化転換による⼼筋分化誘導法の確立


    公益財団法人 アステラス病態代謝研究会, 研究助成金, 橋本 寿之, 研究助成, Research grant, Principal Investigator

display all >>

Awards 【 Display / hide

  • 東京都医師会 医学研究賞

    2021, 東京都医師会

    Type of Award: Awards of National Conference, Council and Symposium

  • 三四会奨励賞

    2020, 慶應義塾大学医学部 

    Type of Award: Keio commendation etc.

  • 第14回循環器再生医科学賞(基礎研究)

    2020, 日本循環器学会

    Type of Award: Awards of National Conference, Council and Symposium

  • 未成年心臓血管病の学究等に対する奨励金

    2019, 公益財団法人 宮田心臓病研究振興基金

    Type of Award: Awards of Publisher, Newspaper Company and Foundation

  • 日本循環制御医学会 総会・学術集会 会長賞

    2019, 日本循環制御医学会

    Type of Award: Awards of National Conference, Council and Symposium

display all >>


Courses Taught 【 Display / hide

  • Cardiology

    2019, Other, Major subject, Lecture, Within own faculty

Educational Activities and Special Notes 【 Display / hide

  • OSCE


    , Special Affairs about A person who has work experience

  • 医学部カリキュラム委員


    , Special Affairs