Hashimoto, Hisayuki



School of Medicine, Center for Preventive Medicine (Shinanomachi)



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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

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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

  • 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.

  • Therapeutic approaches for cardiac regeneration and repair.

    Hashimoto H, Olson EN, Bassel-Duby R

    Nature reviews. Cardiology (Nature Reviews Cardiology)  15 ( 10 ) 585 - 600 2018.10

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  17595002

     View Summary

    © 2018, Macmillan Publishers Ltd., part of Springer Nature. Ischaemic heart disease is a leading cause of death worldwide. Injury to the heart is followed by loss of the damaged cardiomyocytes, which are replaced with fibrotic scar tissue. Depletion of cardiomyocytes results in decreased cardiac contraction, which leads to pathological cardiac dilatation, additional cardiomyocyte loss, and mechanical dysfunction, culminating in heart failure. This sequential reaction is defined as cardiac remodelling. Many therapies have focused on preventing the progressive process of cardiac remodelling to heart failure. However, after patients have developed end-stage heart failure, intervention is limited to heart transplantation. One of the main reasons for the dramatic injurious effect of cardiomyocyte loss is that the adult human heart has minimal regenerative capacity. In the past 2 decades, several strategies to repair the injured heart and improve heart function have been pursued, including cellular and noncellular therapies. In this Review, we discuss current therapeutic approaches for cardiac repair and regeneration, describing outcomes, limitations, and future prospects of preclinical and clinical trials of heart regeneration. Substantial progress has been made towards understanding the cellular and molecular mechanisms regulating heart regeneration, offering the potential to control cardiac remodelling and redirect the adult heart to a regenerative state.

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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

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    © 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

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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)

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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

     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。

Awards 【 Display / hide

  • Young Investigator’s Award

    2013, International Society of Heart Research Japanese Section

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

  • International Poster Prize Award

    2010, International Society of Heart Research World Congress

    Type of Award: Awards of International Conference, Council and Symposium.  Country: 日本